Bicyclic androgen and progesterone receptor modulator compounds and methods

ABSTRACT

The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by AR and PR. More particularly, the invention relates to nonsteroidal compounds and compositions that are high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and antagonists for AR and PR. Also provided are methods of making such compounds and pharmaceutical compositions, as well as critical intermediates used in their synthesis.

This application claims priority to U.S. Provisional Application No.60/150,987, filed Aug. 27, 1999, the entire disclosure of which isincorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to nonsteroidal compounds that are modulators(i.e., agonists, partial agonists and antagonists) of androgen andprogesterone receptors, and to methods for the making and use of suchcompounds.

BACKGROUND OF THE INVENTION

Intracellular receptors (IRs) form a class of structurally-relatedgenetic regulators scientists have named “ligand dependent transcriptionfactors” (R. M. Evans, Science, 240:889, 1988). Steroid receptors are arecognized subset of the IRs, including androgen receptor (AR),progesterone receptor (PR), estrogen receptor (ER), glucocorticoidreceptor (GR), and mineralocoticoid receptor (MR). Regulation of a geneby such factors requires both the IR itself and a corresponding ligand,which has the ability to selectively bind to the IR in a way thataffects gene transcription.

The natural hormones for steroid receptors have been known for a longtime, such as testosterone for AR and progesterone for PR. A syntheticcompound that binds to an IR and mimics the effect of the native hormoneis referred to as an “agonist”, while a compound that inhibits theeffect of the native hormone is called an “antagonist”. The term“modulators” refers to a group of compounds that have a spectrum ofactivities from agonist, partial agonist to antagonist.

Androgen and progesterone receptor modulators are known to play animportant role in health of both men and women. For example, ARantagonists, such as cyproterone acetate, flutamide and casodex, areuseful in the treatment of prostatic hyperplasia and cancer of theprostate. AR agonists, such as fluoxymesterone, are used in thetreatment of hypogonadism. PR agonists, such as medroxyprogesteroneacetate, are used in birth control formulations in combination with thefemale hormone estrogen or a synthetic estrogen analogue. Further,antagonists of PR are potentially useful for contraception and in thetreatment of chronic disorders, such as certain hormone dependentcancers of the breast, ovary and uterus. Due to increased lifeexpectancies, development of tissue selective, safer, orally active ARand PR modulators are desirable to improve quality of life.

A group of hydroquinoline derivatives was recently described as AR andPR modulators (e.g., U.S. Pat. Nos. 5,688,808, 5,688,810, 5,693,646,5,693,647, 5,696,127, 5,696,130). This group of AR and PR modulators wasdeveloped by using cell-based high-throughput assays, termedcotransfection assays. Amino- or hydroxy-trifluoromethylquinolones orcoumarins have been described as fluorescent markers in biologicalsystems. See, e.g., U.S. Pat. No. 4,505,852 and E. R. Bissel et al.,“Synthesis and Chemistry of 7-Amino-4-(trifluoromethyl)coumarin and ItsAmino Acid and Peptide Derivatives”, J. Org. Chem., 45:2283, 1980).Analogues of quinolone, oxindole, benzooxazinone derivatives have beendescribed as cardiotonic agents. See, e.g., U.S. Pat. Nos. 3,993,656;4,415,572; 4,427,654; 4,710,507; 4,728,653; 4,933,336; 5,081,242.

SUMMARY OF THE INVENTION

The present invention is directed to compounds, pharmaceuticalcompositions, and methods for modulating processes mediated by AR andPR. More particularly, the invention relates to nonsteroidal compoundsand compositions that are high affinity, high specificity agonists,partial agonists (i.e., partial activators and/or tissue-specificactivators) and antagonists for AR and PR. Also provided are methods ofmaking such compounds and pharmaceutical compositions, as well ascritical intermediates used in their synthesis.

For a better understanding of the invention, its advantages, and objectsobtained by its use, reference should be had to the accompanyingdescriptive matter, in which preferred embodiments of the invention aredescribed.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In accordance with the present invention and as used herein, thefollowing structure definitions are provided for nomenclature purposes.Furthermore, in an effort to maintain consistency in the naming ofcompounds of similar structure but differing substituents, the compoundsdescribed herein are named according to the following generalguidelines.

The term “alkyl” refers to an optionally substituted straight-chain orbranched-chain hydrocarbon radical having from 1 to about 10 carbonatoms, preferably from 1 to about 6 carbon atoms, and most preferablyfrom 1 to about 4 carbon atoms. Examples of alkyl radical includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, octyl and the like.

The term “alkenyl” refers to a straight-chain or branched-chainhydrocarbon radical having one or more carbon-carbon double-bonds andhaving from 2 to about 10 carbon atoms, preferably from 2 to about 6carbon atoms, and most preferably from 2 to about 4 carbon atoms.Preferred alkeny groups include allyl. Examples of alkenyl radicalsinclude ethenyl, propenyl, 1,4-butadienyl and the like.

The term “allyl” refers to the radical H₂C═CH—CH₂.

The term “alkynyl” refers to a straight-chain or branched-chainhydrocarbon radical having one or more carbon-carbon triple-bonds andhaving from 2 to about 10 carbon atoms. Examples of alkynyl radicalsinclude ethynyl, propynyl, butynyl and the like.

The term “aryl” refers to optionally substituted aromatic ring systems.The term aryl includes monocyclic aromatic rings, polycyclic aromaticring systems, and polyaromatic ring systems. The polyaromatic andpolycyclic ring systems may contain from two to four, more preferablytwo to three, and most preferably two, rings. Preferred aryl groupsinclude 5-or 6-membered aromatic ring systems.

The term “heteroaryl” refers to optionally substituted aromatic ringsystems having one or more heteroatoms such as, for example, oxygen,nitrogen and sulfur. The term heteroaryl may include five- orsix-membered heterocyclic rings, polycyclic heteroaromatic ring systems,and polyheteroaromatic ring systems where the ring system has from twoto four, more preferably two to three, and most preferably two, rings.The terms heterocyclic, polycyclic heteroaromatic, andpolyheteroaromatic include ring systems containing optionallysubstituted heteroaromatic rings having more than one heteroatom asdescribed above (e.g., a six membered ring with two nitrogens),including polyheterocyclic ring systems from two to four, morepreferably two to three, and most preferably two, rings. The termheteroaryl includes ring systems such as, for example, pyridine,quinoline, furan, thiophene, pyrrole, imidazole and pyrazole.

The term “alkoxy” refers to an alkyl ether radical wherein the termalkyl is defined as above. Examples of alkoxy radicals include methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy,tert-butoxy and the like.

The term “aryloxy” refers to an aryl ether radical wherein the term arylis defined as above. Examples of aryloxy radicals include phenoxy,benzyloxy and the like.

The term “cycloalkyl” refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl radical wherein each cyclicmoiety has about 3 to about 8 carbon atoms. Examples of cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andthe like.

The term “cycloalkylalkyl” refers to an alkyl radical as defined abovewhich is substituted by a cycloalkyl radical having from about 3 toabout 8 carbon atoms.

The term “aralkyl” refers to an alkyl radical as defined above in whichone hydrogen atom is replaced by an aryl radical as defined above, suchas, for example, benzyl, 2-phenylethyl and the like.

The terms alkyl, alkenyl, and alkynyl include optionally substitutedstraight-chain, branched-chain, cyclic, saturated and/or unsaturatedstructures, and combinations thereof.

The terms haloalkyl, haloalkenyl and haloalkynyl include alkyl, alkenyland alkynyl structures, as described above, that are substituted withone or more fluorines, chlorines, bromines or iodines, or withcombinations thereof.

The terms heteroalkyl, heteroalkenyl and heteroalkynyl includeoptionally substituted alkyl, alkenyl and alkynyl structures, asdescribed above, in which one or more skeletal atoms are oxygen,nitrogen, sulfur, or combinations thereof.

The substituents of an “optionally substituted” structure include, forexample, one or more, preferably 1 to 4, more preferably 1 to 2 of thefollowing preferred substituents: alkyl, alkenyl, alkynyl, aryl,heteroaryl, alkoxy, aryloxy, cycloalkyl, cycloalkylalkyl, arylalkyl,amino, alkylamino, dialkylamino, F, Cl, Br, I, CN, NO₂, NH₂, NHCH₃,N(CH₃)₂, SH, SCH₃, OH, OCH₃, OCF₃, CH₃, CF₃, C(O)CH₃, CO₂CH₃, CO₂H andC(O)NH₂.

Examples of compounds of the present invention are represented by thosehaving the formula:

wherein:

R¹ and R² each independently represent COR³, CSR³, SO₂R³, NO, NR³R⁴,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ haloalkyl, C₂-C₈haloalkenyl, C₂-C₈ haloalkynyl, C₁-C₈ heteroalkyl, C₂-C₈ heteroalkenyl,C₂-C₈ heteroalkynyl, (CH₂)_(n)R³, aryl, or heteroaryl and wherein thealkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl may beoptionally substituted with F, Cl, Br, I, OR³, NR³R⁴, SR³, SOR³, SO₂R³,C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl, or alternatively,

R¹ and R² may be taken together to form a three- to nine-membered alkyl,alkenyl, heteroalkyl, or heteroalkenyl ring and wherein the alkyl,alkenyl, heteroalkyl, or heteroalkenyl ring may be optionallysubstituted with F, Cl, Br, I, NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkyl orC₁-C₄ heteroalkyl, or

R¹ and R² may be taken together to form one of:

Preferably, R¹ and R² may be taken together to form:

Most preferably, R¹ and R² may be taken together to form:

Most preferably, R¹ and R² may be taken together to form:

R^(A) represents hydrogen, OR^(C), O₂CR^(C), (CH₂)_(n)OR^(C), NHR^(C),NHCOR^(C), F, Cl, Br, I, CN, SCN, SCH₃;

R^(B) represents hydrogen, F, Cl, Br, I, CHF₂, CF₃, C₁-C₆ alkyl, aryl,heteroaryl, wherein the alkyl, aryl and heteroaryl may be optionallysubstituted with F, Cl, Br, I, CN, NO₂, OH, OCH₃, CF₃, C₁-C₆ alkyl;

R^(C) represents hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₁-C₈ haloalkyl, C₁-C₈ heteroalkyl, (CH₂)_(n)R^(D);

R^(D) represents aryl or heteroary, optionally substituted with F, Cl,Br, I, CN, NO₂, OH, OCH₃, CF₃, C₁-C₆ alkyl;

R³ and R⁴ each independently represent hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₁-C₈ haloalkyl, C₁-C₈ heteroalkyl, heteroaryl,or aryl and wherein the alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl,heteroaryl, and aryl may be optionally substituted with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl;

R⁵ represents hydrogen, F, Cl, Br, I, OR³, SR³, SOR³, SO₂R³, NR³R⁴,C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl;

R⁶ represents F, Cl, Br, I, CH₃, CF₃, CHF₂, CFH₂, CN, CF₂Cl, CF₂OR³,OR³, SR³, SOR³, SO₂R³, NR³R⁴, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄ haloalkynyl, C₁-C₄heteroalkyl, C₂-C₄ heteroalkenyl, or C₂-C₄ heteroalkynyl and wherein thealkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl may beoptionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl orC₁-C₄ heteroalkyl;

R⁷ and R⁸ each independently represent hydrogen, F, Cl, Br, I, CN, OR³,NR³R⁴, NR³CR³R⁴CONR³R⁴, C_(n)(R³)_(2n)OR³, SR³, SOR³, SO₂R³, NR³COR⁴,C₁-C₈ alkyl, C₁-C₈ haloalkyl, or C₁-C₈ heteroalkyl;

R⁹ represents hydrogen, F, Br, Cl, I, OR³, NR³R⁴, SR³, SOR³, SO₂R³,C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl;

R¹⁰ represents one of:

R¹¹ represents hydrogen, F, Br, Cl, I, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, NO₂, CN, CF₃, OR³, NR³R⁴, SR³, SOR³, or SO₂R³;

R¹² is F, Br, Cl, I, CN, OR³, SR³, SOR³, SO₂R³, NR³R⁴, C₁-C₄ alkyl,C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl;

R¹³ represents hydrogen, F, Cl, Br, I, CN, OR¹, NHR¹, COR³, CO₂R³, SR¹,SOR³, SO₂R³, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ haloalkyl,C₂-C₈ haloalkenyl, C₂-C₈ haloalkynyl, C₁-C₈ heteroalkyl, C₂-C₈heteroalkenyl, C₂-C₈ heteroalkynyl, (CH₂)_(n)R³, or heteroaryl andwherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, (CH₂)_(n)R³, andheteroaryl may be optionally substituted with F, Cl, Br, I, CN, NO₂,NR¹R³, SR, SOR³, SO₂R³, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄heteroalkyl;

R¹⁴ represents F, Br, Cl, I, CF₃, CHF₂, CH₂F, CF₂Cl, or CF₂OR³;

R¹⁵ represents hydrogen, F, Br, Cl, I, CN, C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ heteroalkyl, OR¹⁶, NR¹⁶R⁴, SR¹⁶, CH₂R¹⁶, COR³, CO₂R³, CONR³R⁴,SOR³, or SO₂R³;

R¹⁶ represents hydrogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈heteroalkyl, aryl, heteroaryl, COR¹⁷, CO₂R¹⁷, or CONR¹⁷R¹⁷;

R¹⁷ represents hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄heteroalkyl;

R¹⁸ and R¹⁹ each independently represent hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl or C₁-C₆ heteroalkyl, or alternatively, R¹⁸ and R¹⁹ may betaken together to form a three- to seven-membered ring;

R²⁰ represents an aryl or heteroaryl wherein the aryl or heteroaryl maybe optionally substituted with F, Cl, Br, CN, OR¹, SR¹, SOR³, SO₂R³,NO₂, NR¹R³, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl;

R²¹ represents CR³R⁴CONR³R⁴, C_(n)(R³)_(2n)OR³, SOR³, SO₂R³, C₂-C₈alkyl, C₂-C₈ haloalkyl, and C₂-C₈ heteroalkyl;

R²² and R²³ each independently represent hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl or C₁-C₆ heteroalkyl, or alternatively R²² and R²³ may betaken together to form a three- to seven-membered ring;

R²⁴ represents hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄heteroalkyl, or OR³;

R²⁵ through R³⁰ each independently represent hydrogen, F, Cl, Br, I,OR³, NR³R⁴, SR³, SOR³, SO₂R³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆heteroalkyl, C₂-C₆ alkynyl or C₂-C₆ alkenyl, and wherein the alkyl,haloalkyl, heteroalkyl, alkynyl, and alkenyl may be optionallysubstituted with F, Cl, Br, I, OR³, NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ heteroalkyl, aryl or heteroaryl and wherein the aryl andheteroaryl may be optionally substituted with F, Cl, Br, I, CN, NO₂, OH,OCH₃, CF₃ or C₁-C₆ alkyl;

Any two of R²⁵ through R³⁰ when taken together can form a three toseven-membered alkyl or alkenyl or heteroalkyl ring; or any four of R²⁵through R³⁰ when taken together can form a fused aromatic ring;

Q represents O or S;

U represents V, OCR²²R²³, SCR²²R²³, NR³CR²²R²³, CR³R⁴CR²²R²³;

V represents O, S, NR³, CR²²R²³, CR³R⁴O, or CR³R⁴S, but, V is not S whenR¹ and R² are both methyl;

W represents O, S, NR³, CR²⁵R²⁶;

X represents O, S or NR¹⁶;

Y represents O, S, NR³, NOR³ or CR³R⁴;

Z represents O, S, NR³, C═O, or CR³R⁴, or optionally Z may represent twohydrogens;

n is 1, 2, 3 or 4; and

m is 1 to 5.

Preferred R¹ and R² groups include COR³, CSR³, SO₂R³, C₁-C₈ alkyl, C₂-C₈alkenyl, C₁-C₈ haloalkyl, C₂-C₈ haloalkenyl, C₂-C₈ heteroalkyl, C₂-C₈heteroalkenyl, (CH₂)_(n)R^(3A), aryl, and heteroaryl, wherein the aryl,or heteroaryl may be optionally substituted with F, Cl, Br, OR³, NR³R⁴,CN, NO₂, SR³, COMe, COCF₃, C₁-C₄ alkyl, C₁-C₄ haloalkyl. Also preferred,R¹ and R² groups may be taken together to form one of:

More preferred R¹ and R² groups include COR, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₁-C₈ haloalkyl, C₂-C₈ haloalkenyl, C₁-C₈ heteroalkyl, CH₂R^(3A), aryland heteroaryl. The aryl or heteroaryl may be optionally substitutedwith F, Cl, Br, OH, OMe, SH, SMe, CN, NO₂, CF₃, Me, COMe, or R¹ and R²groups may be taken together to form:

Most preferably, R¹ and R² groups include C₁-C₈ alkyl, C₂-C₈ alkenyl,C₁-C₈ haloalkyl, C₁-C₈ heteroalkyl, and CH₂R^(3A), or, R¹ and R² groupsmay be taken together to form:

Preferred R³ and R⁴ groups include hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₁-C₈ haloalkyl, and C₁-C₈ heteroalkyl. More preferred R³ and R⁴ groupsinclude hydrogen, C₁-C₆ alkyl and C₁-C₈ haloalkyl. Most preferably, R³and R⁴ each independently is selected from group of hydrogen, C₁-C₆alkyl, and C₁-C₆ haloalkyl.

Preferred R^(3A) groups include aryl and heteroaryl, wherein the aryland heteroaryl may be optionally substituted with halogen, CN, OMe, SMe,C₁-C₄ alkyl, or C₁-C₄ haloalkyl. More preferred R^(3A) groups includeheteroaryl and aryl, wherein the heteroaryl and aryl may be optionallysubstituted with F, Cl, Br, CN, OMe, C₁-C₄ alkyl, or C₁-C₄ haloalkyl.Most preferably, R^(3A) groups include heteroaryl and aryl, wherein theheteroaryl and aryl may be optionally substituted with F, Cl, Br, CN,CF₃, OMe, or C₁-C₄ alkyl.

Preferred R⁵ groups include hydrogen, F, Cl, Br, OH, OMe, C₁-C₄ alkyl,and C₁-C₄ haloalkyl. More preferred R⁵ groups include hydrogen, F, Cl,OH, OMe, C₁-C₄ alkyl, and CF₃. Most preferred R⁵ groups includehydrogen, F, Cl, OH, and OMe.

Preferred R⁶ groups include F, Cl, Br, CH₃, CF₃, CHF₂, CFH₂, CN, CF₂Cl,CF₂OR³, OR³, SR³, NR³R⁴, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl,C₂-C₄ haloalkenyl, C₁-C₄ heteroalkyl, and C₂-C₄ heteroalkenyl. Morepreferred R⁶ groups include F, Cl, Br, CF₃, CHF₂, CFH₂, CN, CF₂Cl,CF₂OMe, and C₁-C₄ alkyl. Most preferred R⁶ groups include F, Cl, C₁-C₄alkyl, CF₃, CHF₂, CFH₂, CF₂Cl, CF₂OMe, and OMe.

Preferred R⁷ groups include hydrogen, F, Cl, Br, OR³, NR³R⁴, SR³, C₁-C₈alkyl, C₁-C₈ haloalkyl, or C₁-C₈ heteroalkyl. More preferred R⁷ groupsinclude hydrogen, F, Cl, Me, OMe, and CF₃. Most preferred R⁷ groupsinclude hydrogen, F, Cl, Me, and OMe.

Preferred R⁸ groups include hydrogen, F, Cl, Br, OR³, NR³R⁴, SR³, C₁-C₈alkyl, C₁-C₈ haloalkyl, and C₁-C₈ heteroalkyl. More preferred R⁸ groupsinclude hydrogen, F, Cl, Br, OR³, NR³R⁴, C₁-C₆ alkyl, C₁-C₆ haloalkyl,and C₁-C₆ heteroalkyl. Most preferred R⁸ groups include hydrogen, F, Cl,Br, OR³, NR³R⁴, C₁-C₆ alkyl, C₁-C₆ haloalkyl.

Preferred R⁹ groups include hydrogen, F, Br, Cl, OR³, NR³R⁴, SR³, C₁-C₄alkyl, and C₁-C₄ haloalkyl. More preferred R⁹ groups include hydrogen,F, Br, OH, Me, OMe, and CF₃. Most preferred R⁹ groups include hydrogen,F, Cl, OH, Me, OMe, and CF₃.

Preferred R¹⁰ groups include:

More preferred R¹⁰ groups include:

Preferred R¹¹ groups include F, Br, Cl, I, C₁-C₆ alkyl, CC₁-C₆haloalkyl, NO₂, CN, CF₃, OH, OMe, NR³R⁴, and SR³. More preferred R¹¹groups include F, Br, Cl, C₁-C₆ alkyl, NO₂, CN, CF₃, OH, OMe.

Preferred R¹² groups include F, Br, Cl, and C₁-C₄ haloalkyl. Morepreferred R¹² groups include F, Br, Cl, CF₃, CF₂H and CFH₂.

Preferred R¹³ groups include hydrogen, F, Cl, Br, I, CN, OR³, NR³R⁴,SR³, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ haloalkyl, C₂-C₈haloalkenyl, C₂-C₈ haloalkynyl, C₁-C₈ heteroalkyl, and (CH₂)_(n)R^(3A).More preferred R¹³ groups include hydrogen, F, Cl, Br, OR³, SR³, C₁-C₈alkyl, C₂-C₈ alkenyl, C₁-C₈ haloalkyl. Most preferred R¹³ groups includehydrogen, F, Cl, Br, C₁-C₄ alkyl, C₂-C₄ alkenyl, or C₁-C₈ haloalkyl.

Preferred R¹³A groups include NHR¹ or heteroaryl, wherein the heteroarylmay be optionally substituted with F, Cl, Br, CN, NMe₂, NO₂, CF₃, Me orOMe. More preferred R¹³A is NHR¹.

Preferred R¹⁴ groups include F, Br, Cl, CF₃, CHF₂, CH₂F, CF₂Cl, andCF₂OMe. More preferred R¹⁴ groups include F, Cl, CF₃, CHF₂, CH₂F, andCF₂Cl. Most preferred R¹⁴ groups include Cl, CF₃, CHF₂, CH₂F, and CF₂Cl.

Preferred R¹⁵ groups include F, Br, Cl, CN, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ heteroalkyl, OR¹⁶, NR¹⁶R⁴, and SR¹⁶. More preferred R¹⁵groups include F, Cl, CN, OR¹⁶, and SR¹⁶. Most preferred R¹⁵ groupsinclude Cl, OR¹⁶, NR¹⁶R⁴ and SR¹⁶.

Preferred R¹⁶ groups include hydrogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl,C₁-C₈ heteroalkyl, COR¹⁷, CO₂R¹⁷, and CONR¹⁷R¹⁷. More preferred R¹⁶groups include hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, COR¹⁷, CO₂R¹⁷,and CONR¹⁷R¹⁷. Most preferred R¹⁶ groups include hydrogen, C₁-C₆ alkyl,COR¹⁷; CO₂R¹⁷, and CONR¹⁷R¹⁷.

Preferred R¹⁷ groups include C₁-C₄ alkyl, C₁-C₄ haloalkyl and C₁-C₄heteroalkyl.

Preferred R¹⁸ and R¹⁹ groups include C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆heteroalkyl and R¹⁸ and R¹⁹ may be taken together to form a four- toseven-membered ring. More preferred R¹⁸ and R¹⁹ groups include C₁-C₆alkyl, and C₁-C₆ haloalkyl and R¹⁸ and R¹⁹ may be taken together to forma five- to six-membered ring. Most preferred R¹⁸ and R¹⁹ groups includeC₁-C₄ alkyl, C₁-C₄ haloalkyl and R¹⁸ and R¹⁹ may be taken together toform a five- to six-membered ring.

Preferred R²⁰ groups include aryl and heteroaryl. The aryl or heteroarylmay be optionally substituted with F, Cl, Br, CN, NO₂, CF₃ and C₁-C₄alkyl.

Preferred R²¹ groups include C₂-C₈ alkyl, C₂-C₈ haloalkyl, and C₂-C₈heteroalkyl. More preferred R²¹ groups include C₂-C₈ alkyl, and C₂-C₈haloalkyl.

Preferred R²² and R²³ groups include hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, and C₁-C₆ heteroalkyl and R²² and R²³ groups may be takentogether to form a three- to seven-membered ring. More preferred R²² andR²³ groups include hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl and R²² andR²³ groups taken together to form a four- to six-membered ring.

Preferred R²⁴ groups include hydrogen and OR³. More preferred R²⁴ groupsinclude hydrogen and OH.

Preferred R²⁵, R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ groups include hydrogen, F,Cl, Br, OR³, NR³R⁴, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, andC₂-C₆ alkenyl, wherein the alkyl, haloalkyl, heteroalkyl, alkynyl, oralkenyl may be optionally substituted with F, Cl, Br, OR³, NR³R⁴, arylor heteroaryl and the aryl and heteroaryl may be optionally substitutedwith F, Cl, Br, CN, NO₂, OH, OCH₃, CF₃ or C₁-C₆ alkyl. Also preferred isany two of R²⁵, R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ groups taken together to forma three- to seven-membered alkyl or alkenyl or heteroalkyl ring. Alsopreferred is any four of R²⁵, R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ groups takentogether to form a fused aromatic ring. More preferred R²⁵ through R³⁰groups include hydrogen, F, Cl, OH, OMe, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl and C₂-C₆ alkenyl. Also more preferred is any two ofR²⁵, R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ groups taken together to form a four tosix-membered alkyl or alkenyl ring. Also more preferred is any four ofR²⁵, R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ groups taken together to form a fusedaromatic ring. Most preferred R²⁵ through R³⁰ groups include hydrogen,F, Cl, OH, OMe, C₁-C₄ alkyl, and C₁-C₄ haloalkyl.

Preferably Q is O.

Preferred U groups include V, OCR²²R²³, NR³CR²²R²³, CR³R⁴CR²²R²³.

Preferred V groups include CR²²R²³, CR³R⁴O, and CR³R⁴S.

Preferred W groups include O, NR³, and CR³R⁴. More preferred W groupsinclude O, and CR³R⁴. Most preferably, W is O.

Preferred X groups include S and NR¹⁶. More preferred X groups include Oand NR¹⁶. Most preferably, X is NR¹⁶.

Preferred Y groups include O, S, NR³, and NOR³. More preferred Y groupsinclude O, S, and NOR³. Most preferably, Y is O or S.

Preferred Z groups include O, S, NR³, CR²⁵R²⁶ and two hydrogens. Morepreferred Z groups include O, CR²⁵R²⁶ and two hydrogens. Mostpreferably, Z groups include O, CR³R⁴ and two hydrogens.

Preferably, n is 1 or 2.

Preferably, m is 1 to 4. More preferably, m is 1 to 3.

In a preferred embodiment of the invention, R¹ and R² are eachindependently selected from the group of COR³, CSR³, SO₂R³, NO, NR³R⁴,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ haloalkyl, C₂-C₈haloalkenyl, C₂-C₈ haloalkynyl, C₁-C₈ heteroalkyl, C₂-C₈ heteroalkenyl,C₂-C₈ heteroalkynyl, (CH₂)_(n)R^(3A), aryl, and heteroaryl, wherein thealkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl areoptionally substituted with F, Cl, Br, I, OR³, NR³R⁴, CN, NO₂, SR³,SOR³, SO₂R³, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl. R³ andR⁴ are each independently hydrogen or optionally substituted C₁-C₆alkyl. R^(3A) is optionally substituted alkyl or heteroaryl. R⁵ isselected from the group of hydrogen, halogen and optionally substitutedC₁-C₆ alkyl. R⁷ and R⁸ are each independently hydrogen or halogen; andR⁹ is hydrogen or halogen. R¹¹ is selected from the group of halogen,CN, NO₂ and optionally substituted C₁-C₆ haloalkyl. R¹² is halogen oroptionally substituted haloalkyl. R¹³ is selected from the group ofhydrogen C₁-C₆ alkyl and C₁-C₆ heteroalkyl, wherein said C₁-C₆ alkyl andC₁-C₆ heteroalkyl are optionally substituted. R¹⁵is halogen or OR¹⁶. R¹⁸and R¹⁹ are each independently optionally substituted C₁-C₆ alkyl; orR¹⁸ and R¹⁹ taken together form a five- to six-membered ring. R²² andR²³ are each independently hydrogen or optionally substituted C₁-C₆alkyl; or R²² and R²³ together form a three- to seven-membered ring. R²⁵through R³⁰ are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, wherein said C₁-C₆ alkyl and C₁-C₆ haloalkyl are optionallysubstituted; Y is selected from the group of O, S, and NR³; and m is 1to 3.

In another preferred embodiment of the invention R¹ and R² takentogether form a three- to nine-membered alkyl, alkenyl, heteroalkyl, orheteroalkenyl ring, wherein the alkyl, alkenyl, heteroalkyl, orheteroalkenyl ring are optionally substituted with F, Cl, Br, I, OR³,NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl. R³ and R⁴ areeach independently hydrogen or optionally substituted C₁-C₆ alkyl.R^(3A) is optionally substituted alkyl or heteroaryl. R⁵ is selectedfrom the group of hydrogen, halogen and optionally substituted C₁-C₆alkyl. R⁷ and R⁸ are each independently hydrogen or halogen. R⁹ ishydrogen or halogen. R¹¹ is selected form the group of halogen, CN, NO₂and optionally substituted C₁-C₆ haloalkyl. R¹² is halogen or optionallysubstituted haloalkyl. R¹³ is selected from the group of hydrogen, C₁-C₆alkyl and C₁-C₆ heteroalkyl, wherein said C₁-C₆ alkyl and C₁-C₆heteroalkyl are optionally substituted. R¹⁵ is halogen or OR¹⁶, R¹⁸ andR¹⁹ are each independently optionally substituted C₁-C₆ alkyl; or R¹⁸and R¹⁹ taken together form a five- to six-membered ring. R²² and R²³are each independently hydrogen or optionally substituted C₁-C₆ alkyl;or R²² and R²³ together form a three- to seven-membered ring. R²⁵through R³⁰ are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, wherein said C₁-C₆ alkyl and C₁-C₆ haloalkyl are optionallysubstituted. Y is selected from the group of O, S, and NR³; and m is 1to 3.

In still another preferred embodiment of the invention, R¹ and R² takentogether form one of:

R³ and R⁴ are each independently hydrogen or optionally substitutedC₁-C₆ alkyl. R^(3A) is optionally substituted alkyl or heteroaryl. R⁵ isselected from the group of hydrogen, halogen and optionally substitutedC₁-C₆ alkyl. R⁷ and R⁸ are each independently hydrogen or halogen. R⁹ ishydrogen or halogen. R¹¹ is selected form the group of halogen, CN, NO₂and optionally substituted C₁-C₆ haloalkyl. R¹² is halogen or optionallysubstituted haloalkyl. R¹³ is selected from the group of hydrogen C₁-C₆alkyl and C₁-C₆ heteroalkyl, wherein said C₁-C₆ alkyl and C₁-C₆heteroalkyl are optionally substituted. R¹⁵ is halogen or OR¹⁶, R¹⁸ andR¹⁹ are each independently optionally substituted C₁-C₆ alkyl; or R¹⁸and R¹⁹ taken together form a five- to six-membered ring. R²² and R²³are each independently hydrogen or optionally substituted C₁-C₆ alkyl;or R²² and R²³ together form a three- to seven-membered ring. R²⁵through R³⁰ are each independently hydrogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, wherein said C₁-C₆ alkyl and C₁-C₆ haloalkyl are optionallysubstituted; Y is selected from the group of O, S, and NR³; and m is 1to 3.

The present invention further provides methods of modulating processesmediated by AR or PR or combinations thereof comprising administering toa patient an effective amount of a pharmaceutical composition of thepresent invention comprising one or more compounds represented by thosehaving the following formulas as well as pharmaceutical compositions ofthe above compounds:

wherein:

R¹ and R² each independently represent COR³, CSR³, SO₂R³, NO, NR³R⁴,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ haloalkyl, C₂-C₈haloalkenyl, C₂-C₈ haloalkynyl, C₁-C₈ heteroalkyl, C₂-C₈ heteroalkenyl,C₂-C₈ heteroalkynyl, (CH₂)_(n)R³, aryl, or heteroaryl and wherein thealkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkynyl, aryl,and heteroaryl may be optionally substituted with F, Cl, Br, I, OR³,NR³R⁴, SR³, SOR³, SO₂R³ C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄heteroalkyl, or alternatively,

R¹ and R² may be taken together to form a three- to nine-membered alkyl,alkenyl, heteroalkyl, or heteroalkenyl ring and wherein the alkyl,alkenyl, heteroalkyl, and heteroalkenyl ring may be optionallysubstituted with F, Cl, Br, I, OR³, NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkylor C₁-C₄ heteroalkyl, or

R¹ and R² may be taken together to form one of:

R³ and R⁴ each independently represent hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₁-C₈ alkynyl, C₁-C₈ haloalkyl, C₁-C₈ heteroalkyl, heteroaryl,or aryl and wherein the alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl,heteroaryl, and aryl may be optionally substituted with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl;

R⁵ represents hydrogen, F, Cl, Br, I, OR³, SR³, SOR³, SO₂R³, NR³R⁴,C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl;

R⁷ and R⁸ each independently represent hydrogen, F, Cl, Br, I, CN, OR³,NR³R⁴, NR³CR³R⁴CONR³R⁴, C_(n)(R³)_(2n)OR³, SR³, SOR³, SO₂R³, NR³COR⁴,C₁-C₈ alkyl, C₁-C₈ haloalkyl, or C₁-C₈ heteroalkyl;

R⁹ represents hydrogen, F, Br, Cl, I, OR³, NR³R⁴, SR³, a C₁-C₄ alkyl,C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl;

R¹¹ represents hydrogen, F, Br, Cl, I, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, NO₂, CN, CF₃, OR³,NR³R⁴, SR³, SOR³ or SO₂R³;

R¹⁵ represents hydrogen, F, Br, Cl, I, CN, C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ heteroalkyl, OR¹⁶, NR¹⁶R⁴, SR¹⁶, CH₂R¹⁶, COR³, CO₂R³, CONR³R⁴,SOR³, or SO₂R³;

R¹⁶ represents hydrogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₁-C₈heteroalkyl, aryl, heteroaryl, COR¹⁷, CO₂R¹⁷, or CONR¹⁷R¹⁷;

R¹⁷ represents hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄heteroalkyl;

R¹⁸ and R¹⁹ each independently represent hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl or C₁-C₆ heteroalkyl, or alternatively, R¹⁸ and R¹⁹ may betaken together to form a three- to seven-membered ring;

R²² and R²³ each independently represent hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl or C₁-C₆ heteroalkyl, or alternatively, R²² and R²³ may betaken together to form a three- to seven-membered ring;

R²⁴ represents hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄heteroalkyl, or OR³;

R²⁵ through R³⁰ each independently represent hydrogen, F, Cl, Br, I,OR³, NR³R⁴, SR³, SOR³, SO₂R³, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆heteroalkyl, C₂-C₆ alkynyl or C₂-C₆ alkenyl, and wherein the alkyl,haloalkyl, heteroalkyl, alkynyl, and alkenyl may be optionallysubstituted with F, Cl, Br, I, OR³, NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ heteroalkyl, aryl or heteroaryl and wherein the aryl andheteroaryl may be optionally substituted with F, Cl, Br, I, CN, NO₂, OH,OCH₃, CF₃ or C₁-C₆ alkyl;

Any two Rs of R²⁵ through R³⁰ when taken together can form a three toseven-membered alkyl or alkenyl or heteroalkyl ring; or any four Rs ofR²⁵ through R³⁰ when taken together can form a fused aromatic ring;

R³¹ represents hydrogen, F, Cl, Br, I, CN, OR¹, NHR¹, COR³, CO₂R³, SR¹,SOR³, SO₂R³, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ haloalkyl, C₂-C₈haloalkenyl, C₁-C₈ heteroalkyl, C₂-C₈ heteroalkenyl, C₂-C₈ alkynyl,C₂-C₈ haloalkynyl, C₂-C₈ heteroalkynyl, (CH₂)_(n)R³ or heteroaryl andwherein the alkyl, alkenyl, haloalkyl, haloalkenyl, heteroalkyl,heteroalkenyl, allyl, alkynyl, haloallyl, haloalkynyl, heteroalkynyl,(CH₂)_(n)R³, and heteroaryl may be optionally substituted with F, Cl,Br, I, CN, OR¹, NO₂, NR¹R³, SR¹, SOR³, SO₂R³, C₁-C₄ alkyl, C₁-C₄haloalkyl, or C₁-C₄ heteroalkyl or optionally,

R³¹ represents one of:

R⁴² represents hydrogen, F, Cl, Br, I, CH₃, CF₃, CHF₂, CFH₂, CN, CF₂Cl,CF₂OR³, OR³, SR³, SOR³, SO₂R³, NR³R⁴, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄ haloalkynyl, C₁-C₄heteroalkyl, C₂-C₄ heteroalkenyl, or C₂-C₄ heteroalkynyl, and whereinthe alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl may beoptionally substituted with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl orC₁-C₄ heteroalkyl;

M represents O, S, NR¹⁶;

U represents O, S, NR³, CR²²R²³, CR³R⁴O, or CR³R⁴S;

W represents O, S, NR³, CR²²R²³;

X represents O, S or NR¹⁶, but when R³¹ is an aryl or heteroaryl, X isnot NR¹⁶;

Y represents O, S, NR¹⁶, NOR¹⁶ or CR¹¹⁶R¹⁷;

Z represents O, S, NR³, C═O, or CR³R⁴, or optionally Z may represent twohydrogens;

n is 1, 2 or 3; and

m is 1 to 5.

In a preferred aspect, the present invention provides a pharmaceuticalcomposition comprising an effective amount of an AR or PR modulatingcompound of formulas I through XIII shown above wherein R¹ through R⁴²,M, Q, U, V, W, X, Y and Z all have the same definitions as given above.

In a further preferred aspect, the present invention comprises a methodof modulating processes mediated by ARs or PRs or combinationscomprising administering to a patient an effective amount of a compoundof the formulae I through XIII shown above wherein R¹ through R⁴², M, Q,U, V, W, X, Y and Z all have the same definitions as given above.

Any of the compounds of the present invention can be synthesized aspharmaceutically acceptable salts for incorporation into variouspharmaceutical compositions. As used herein, pharmaceutically acceptablesalts include, but are not limited to, hydrochloric, hydrobromic,hydroiodic, hydrofluoric, sulfuric, citric, maleic, acetic, lactic,nicotinic, succinic, oxalic, phosphoric, malonic, salicylic,phenylacetic, stearic, pyridine, ammonium, piperazine, diethylamine,nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc,lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric,triethylamino, dimethylamino, and tris(hydroxymethyl)aminomethane.Additional pharmaceutically acceptable salts are known to those skilledin the art.

AR agonist, partial agonist and antagonist compounds (includingcompounds with tissue-selective AR modulator activity) of the presentinvention are useful in the treatment of hypogonadism (agonist), malehormone replacement therapy (agonist), wasting diseases (agonist),cancer cachexia (agonist), male contraception, hirsutism (antagonist),stimulation of hematopoiesis (agonist), acne (antagonist), male-patternbaldness (antagonist), prostatic hyperplasia (antagonist), varioushormone-dependent cancers, including, without limitation, prostate(antagonist),and breast cancer and as anabolic agents (agonist). It isunderstood by those of skill in the art that a partial agonist may beused where agonist activity is desired, or where antagonist activity isdesired, depending upon the AR modulator profile of the particularpartial agonist.

PR agonist, partial agonist and antagonist compounds of the presentinvention are useful in female hormone replacement therapy and asmodulators of fertility (e.g., as contraceptives, contragestationalagents or abortifacients), either alone or in junction with ERmodulators. The PR modulators are also useful in the treatment ofdysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyomas(uterine fibroids), hot flashes, mood disorders, meningiomas as well asin various hormone-dependent cancers, including, without limitation,cancers of ovary, breast, endometrium and prostate.

It is understood by those skilled in the art that although the compoundsof the present invention are typically employed as selective agonists,partial agonists or antagonists, there may be instances where a compoundwith a mixed steroid receptor profile is preferred.

Furthermore, it is understood by those skilled in the art that thecompounds of the present invention, including pharmaceuticalcompositions and formulations containing these compounds, can be used ina wide variety of combination therapies to treat the conditions anddiseases described above. Thus, the compounds of the present inventioncan be used in combination with other hormones and other therapies,including, without limitation, chemotherapeutic agents such ascytostatic and cytotoxic agents, immunological modifiers such asinterferons, interleukins, growth hormones and other cytokines, hormonetherapies, surgery and radiation therapy.

Representative AR modulator compounds (i.e., agonists and antagonists)according to the present invention include:

6-Amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 200);

6-Propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 204);

6-Isopropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 205);

6-Isobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 206);

6-(2,2-Dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 207);

6-Cyclopentylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 208);

6-(2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 209);

6-(2,2,3,3,3-Pentafluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 210);

6-(2,2-Difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound211);

6-(2-Chloro-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 212);

6-Acetylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 213);

6-Trifluoroacetylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound214);

6-Benzoylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 215);

6-Dimethylacetylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound216);

6-Dimethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 217);

6-Diethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 218);

6-Dipropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 219);

6-Dibutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 220);

6-Diisobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 221);

6-(bis-Cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 222);

6-(bis-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 223);

6-(bis-2,2,3,3,3-Pentafluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 224);

6-(bis-2-Chloro-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 225);

6-(bis-2-Bromoethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound226);

6-(N-2,2,2-Trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 227);

6-(bis-N-2,2,2-Trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 228);

6-(N-2,2,2-Chlorodifluoroethyl-N-2,2,2-Trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 229);

6-(bis-N-2,2-Difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 230);

6-(N-2,2-Dichloroethyl-N-2,2,2-trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 231);

6-(bis-N-2,2-Dichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 232);

6-(N-2,2-Dichloroethyl-N-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 233);

6-(N-2,2-Dichloroethyl-N-2,2,2-chlorodifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 234);

6-(N-Isopropyl-N-methyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 235);

6-(N-Methyl-N-cyclopentyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 236);

6-(N-Methyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 237);

6-(N-Ethyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound238);

6-(N-Ethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 239);

6-(N-Ethyl-N-1-methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 240);

6-(N-Ethyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 241);

6-(N-Ethyl-N-2,2-dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 242);

6-(N-Ethyl-N-cyclopentyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 243);

6-(N-Ethyl-N-1-acetylethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 244);

(±)-6-(N-Ethyl-N-1-methyl-2-hydroxypropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 245);

6-(N-Ethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(H11)-quinolinone(Compound 246);

6-(N-Ethyl-N-3-furylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 247);

(±)-6-(N-Ethyl-N-2,2-dimethoxyisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 248);

6-(N-Isopropyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 249);

6-(N-2-Hydroxyethyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 250);

(±)-6-(N-Propyl-N-1-methylbutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 251);

(±)-6-(N-Propyl-N-1,2-dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 252);

6-(N-Propyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 253);

6-(N-Propyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 254);

(±)-6-(N-Propyl-N-1-methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 255);

6-(N-2-Hydroxyethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 256);

6-(N-Isopropyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 257);

6-(N-Methyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 258);

6-(N-2,2,2-trifluoroethyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 259);

6-(N-2,2,2-trifluoroethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 260);

6-(N-2,2,2-Trifluoroethyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 261);

(±)-6-(N-2,2,2-Trifluoroethyl-N-1-methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 262);

(±)-6-(N-2,2,2-Trifluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 263);

(+)-6-(N-2,2,2-Trifluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 264);

(−)-6-(N-2,2,2-Trifluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 265);

6-(N-2,2,2-Trifluoroethyl-N-3-furfuryl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 266);

6-(N-2,2,2-Trifluoroethyl-N-3-thiophenemethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 267);

6-(N-2,2,2-Trifluoroethyl-N-3,3-dimethylbutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 268);

6-(N-2,2,2-Trifluoroethyl-N-2-thiophenemethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 269);

6-(N-2,2,2-Trifluoroethyl-N-2-furfuryl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 270);

6-(N-Butyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 271);

6-(bis-N,N-Benzyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound272);

6-(N-2,2,2-Trifluoroethyl-N-cyclobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone12 (Compound 273);

6-(N-2,2,2-Trifluoroethyl-N-2,2-dichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 274);

6-(N-2,2,2-Trifluoroethyl-N-2-chloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 275);

6-(N-Benzyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 276);

6-(N-4-Fluorobenzyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 277);

6-(N-Propyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 278);

6-(N-2,2,3,3,3-Pentafluoropropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 279);

6-Diallylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 280);

6-(N-Isobutyl-N-allyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 281);

6-(N-Isopropyl-N-allyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 282);

6-(N-Allyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 283);

6-Allylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 284);

6-(N-Allyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 285);

6-(N-Allyl-N-2,2,2-trifluoroacetyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 286);

6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroacetyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 287);

6-(N-Allyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound288);

(±)-6-(N-2-Hydroxyisopropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 289);

(±)-6-(N-Isobutyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 290);

6-(N-2,2-Difluoroethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 291);

6-(N-2,2-Dimethylpropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 292);

6-(N-2,2-Difluoro-2-chloroethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 293);

6-(N-2,2-Difluoro-2-chloroethyl-N-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 294);

6-(N-2,2,2-Trifluoroethyl-N-methylsufonyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 295);

1-Methyl-6-(N-propyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 296);

1-Methyl-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 297);

1-Ethyl-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 298);

6-(N-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-thioquinolinone(Compound 299);

6-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-thioquinolinone(Compound 300);

(±)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 301);

(+)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 302);

(−)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 303);

6-Methoxythiocarbonylmercapto-4-trifluoromethyl-2(1H)-quinolinone(Compound 304);

6-Mercapto-4-trifluoromethyl-2(1H)-quinolinone (Compound 305);

6-(1,1-Dimethyl-2-propynyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 306);

6-tert-Butylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 307);

6-Bromo-4-trifluoromethyl-2(1H)-quinolinone (Compound 308);

6-Bromo-4-trifluoromethyl-2-isopropyloxyquinoline (Compound 309);

6-tert-Butylamino-2-isopropyloxy-4-trifluoromethylquinolines (Compound310);

6-(1-Piperdinyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound 311);

6-(1-Pyrrolidinyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound 312);

6-(1-Morpholino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 313);

(±)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 314);

(+)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 315);

(−)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 316);

6-(N-phenylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 317);

6-(N-phenyl-N-ethylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound319);

6-(N-phenyl-N-ethylamino)-4-trifluoromethyl-2-isopropyloxyquinoline(Compound 320);

6-(N-phenyl-N-2,2,2-trifluoroethylamino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 321);

(±)-6-(3-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 322);

6-(4-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound323);

6-(cis-3,5-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 324);

6-(2,6-cis-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 325);

6-(2,6-trans-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 326);

(±)-6-(2-Methyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 327);

6-(2,5-cis-Dimethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 328);

(±)-6-(2,5-trans-Dimethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 329);

6-(1-Azepano)-4-trifluoromethyl-2(1H)-quinolinone (Compound 330);

(±)-6-(2-Hydroxymethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 331);

6-(2,5-cis-Dimethyl-1-pyrrolino)-4-trifluoromethyl-2(11)-quinolinone(Compound 332);

(±)-6-(2-Propyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 333);

(±)-6-(2-Methoxymethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 334);

(±)-6-(2-Ethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 335);

6-(1-Cycloheptylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound336);

(±)-6-(2-Ethoxycarbonyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 337);

(±)-6-(2-Isopropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 338);

(±)-6-(2-Hydroxycarbonyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 339);

6-(3,5-cis-Dimethyl-1-piperazino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 340);

(±)-6-(2-Benzyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 341);

(±)-6-(5-Methyl-2-oxo-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 342);

(±)-6-(2-(2-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 343);

(±)-6-(3-Hydroxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone-(Compound344);

(±)-6-(3-Acetyloxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 345);

(±)-6-(3-Hydroxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 346);

6-(1-Indolino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 347);

6-(1-Tetrahydroquinolino)-4-trifluoromethyl-2(1H)-quinolinone (Compound348);

6-(2-Tetrahydroisoquinolino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 349);

(±)-6-(1,3,3-Trimethyl-6-azabicyclo[3.2.1]octanyl-6-)-4-trifluoromethyl-2(1H)-quinolinone(Compound 350);

(±)-6-(2-Trifluoromethyl-5-cis-methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 351);

(±)-6-(2-Trifluoromethyl-5-trans-methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 352);

6-N-(1-Hydroxyisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 353);

(±)-6-(2-Trifluoromethyl-5-cis-ethyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone270 (Compound 354);

(±)-6-(2-Trifluoromethyl-5-trans-ethyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 355);

(±)-6-(5-Methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 356);

6-(2,5-Dimethyl-1-pyrrolyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 357);

6-(N-2,2,2-Trifluoroethyl-N-3,3,3-trifluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 358);

6-(N-3,3,3-Trifluoropropyl)amino-4-trifluoromethyl-2-isopropyloxyquinoline(Compound 360);

6-bis-N,N-Thiomethoxymethylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 361);

6-bis-N,N-Thiomethoxymethylamino-4-trifluoromethyl-2-thiomethoxymethyloxyquinoline(Compound 362);

(±)-6-(2,5-trans-Diethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 363);

6-(2,5-cis-Diethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 364);

(±)-6-(2,5-trans-Dipropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 365);

6-(2,5-cis-Dipropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 366);

6-(2,5-Dipropyl-1-pyrrolo)-4-trifluoromethyl-2(1H)-quinolinone (Compound367);

6-(2,5-cis-Dibutyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 368);

(±)-6-(2,5-trans-Dibutyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 369);

6-(2,6-cis-Diethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 370);

(±)-6-(2,6-trans-Diethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 371);

6-(2,6-cis-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 372);

(±)-6-(2,6-trans-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 373);

6-(N-Propyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 374);

6-Amino-4-methyl-2(1H)-quinolinone (Compound 375);

6-(bis-2,2,2 Trifluoroethyl)amino-4-methyl-2(1H)-quinolinone (Compound377);

6-(2,5-Dimethyl-1-pyrrolyl)-4-methyl-2(1H)-quinolinone (Compound 378);

(±)-6-(2,5-trans-dimethyl-1-pyrrolidino)-4-methyl-2(1H)-quinolinone(Compound 379);

6-(2,5-cis-dimethyl-1-pyrrolidino)-4-methyl-2(1H)-quinolinone (Compound380);

6-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 381);

6-(N-2,2,2-Chlorodifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 382);

6-(bis-N,N-2,2,2-Chlorodifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 383);

6-(N-2,2,2-Chlorodifluoroethyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 384);

6-N-Ethylamino-4-methyl-2(1H)-quinolinone (Compound 385);

6-(N-Ethyl-N-2,2 2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 386);

6-N,N-Diethylamino-4-methyl-2(1H)-quinolinone (Compound 387);

6-(bis-2,2,2-trifluoroethyl)amino-4-ethyl-2(1H)-quinolinone (Compound388);

6-Amino-4-ethyl-2(1H)-quinolinone (Compound 389);

6-(bis-2,2,2-trifluoroethyl)amino-4-isopropyl-2(1H)-quinolinone(Compound 391);

6-Amino-4-isopropyl-2(1H)-quinolinone (Compound 392);

7-Fluoro-6-(bis-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 393);

7-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 394);

5-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 395);

6-Amino-7-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 396);

8-Fluoro-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 397);

8-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 316);6-Amino-8-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 399);

8-Fluoro-6-(N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 400);

8-Fluoro-6-(N-2,2,2-trifluoroethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 401);

6-Amino-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 402);

3-Fluoro-6-(2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 403);

3-Fluoro-6-(bis-2,2,2-trifluorofluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 404);

6-(bis-Isobutylamino)-4-methyl-2(1H)-quinolinone (Compound 405);

3-Fluoro-6-(N-methyl-N-2,2,2-trifluorofluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 406);

7-Bromo-6-isopropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound407);

6-Amino-7-bromo-4-trifluoromethyl-2(1H)-quinolinone (Compound 408);

6-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-hydroxy-2(1H)-quinolinone(Compound 409);

6-amino-4-hydroxy-2(1H)-quinolinone (Compound 410);

6-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-methoxy-2(1H)-quinolinone(Compound 411);

6-amino-4-methoxy-2(1H)-quinolinone (Compound 412);

6-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-difluoromethyl-2(1H)-quinolinone(Compound 413);

6-amino-4-difluoromethyl-2(1H)-quinolinone (Compound 414);

6-(bis-N,N-2,2,2-Trifluoroethyl)amino-2(1H)-quinolinone (Compound 415);

6-amino-2(1H)-quinolinone (Compound 416);

4-Chloro-6-(bis-N,N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone(Compound 417);

6-amino-4-chloro-2(1H)-quinolinone (Compound 418);

7-Methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 419);

5,7-Dimethoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 420);

(R)-6-(2-Hydroxymethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 421);

(R)-6-(2-Methoxycarbonyl-1-pyrrolidino)-4-trifluoromethyl-2-isopropyloxyquinoline(Compound 422);

(R)-6-(2-Methoxymethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 423);

(±)-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 424);

(±)-6-(2-Cyanothiomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 425);

(±)-6-(2-Thiomethoxymethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 426);

(±)-6-(2-Cyanomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 427);

(±)-6-(2-Bromomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 428);

(±)-6-(2-Iodomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 429);

(+)R-6-(2-Iodomethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 430);

(±)-6-(2-Fluoromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 431);

(+)S-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 432);

(−)R-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 433);

(+)R-6-(2-Chloromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 434);

(−)S-6-(2-Chloromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 435);

R-6-(2-Difluoromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 436);

(±)-6-(2l-(1l-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 437);

(±)-6-(2l-(1u-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 438);

(±)-6-(2-Formyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 439);

(±)-6-(2-Difluoromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 440);

(±)-6-(2-Aminomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 441);

(R)-6-(2-Vinyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 442);

(R)-6-(2-Formyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 443);

(±)-6-(2-Vinyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 444);

(±)-6-(2-Benzyloxyethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 445);

(±)-6-(2-(2,2-Difluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 446);

(±)-6-(2-Trifluoroacetamidomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 447);

(±)-6-(2-(2-Ethoxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 448);

(±)-6-(2-(4-Trifluoromethyl)benzyloxyethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 449);

(+)-6-(2R-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 450);

(−)6-(2R-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 451);

6-(2S-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 452);

6-(2S-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 453);

(±)-6-(2l-(1l-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 454);

(±)-6-(2l-(1u-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 455);

(−)-6-(2S-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 456);

(+)-6-(2R-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 457);

(+)-6-(2R-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 458);

(−)-6-(2S-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 459);

(±)-6-(2l-(1l-Acetyloxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 460);

(±)-6-(2l-(1u-Acetyloxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 461);

(±)-6-(2l-(1u-Methoxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 462);

(±)-6-(2l-(1l-Methoxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 463);

7-Methoxy-6-(N-methyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 464);

4-Amino-2-methoxy-N-2,2,2-trifluoroethylaniline (Compound 466);

7-Methoxy-6-(N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 467);

7-Methoxy-6-(N-ethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 468);

7-Hydroxy-6-(2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 469);

6-(N-Cyclopropylmethyl-N-2,2,2-trifluoroethyl)amino-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 470);

6-(N-Cyclopropylmethyl-N-2,2,2-trifluoroethyl)amino-7-hydroxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 471);

6-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 472);

6-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-7-hydroxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 473);

6-(bis-2,2,2-Trifluoroethyl)amino-4-trifluoromethylcoumarin (Compound474);

6-Amino-4-trifluoromethylcoumarin (Compound 475);

(±)-3,4-Dihydro-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethylcoumarin(Compound 476);

6-(2,2,2-trifluoroethyl)amino-4-trifluoromethylcoumarin (Compound 477);

6-(N-Isopropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethylcoumarin(Compound 478);

6-N-Isobutylamino-4-trifluoromethylcoumarin (Compound 479);

6-N,N-Diethylamino-4-trifluoromethylcoumarin (Compound 480);

6-N,N-Dipropylamino-4-trifluoromethylcoumarin (Compound 481);

6-N-Propylamino-4-trifluoromethylcoumarin (Compound 482);

6-(N-Isobutyl-N-propylamino)-4-trifluoromethylcoumarin (Compound 483);

6-(N-2,2,2-Trifluoroethyl-N-propylamino)-4-trifluoromethylcoumarin(Compound 484);

1,4-Dihydro-4,4-dimethyl-6-methylamino-1,3-benzo[d]oxazin-2-one(Compound 485);

6-Amino-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound487);

1,4-Dihydro-4,4-dimethyl-6-dimethylamino-1,3-benzo[d]oxazin-2-one(Compound 488);

1,4-Dihydro-4,4-dimethyl-6-dipropylamino-1,3-benzo[d]oxazin-2-one(Compound 489);

1,4-Dihydro-4,4-dimethyl-6-(bis-N,N-2,2,2-trifluoroethyl)amino-1,3-benzo[d]oxazin-2-one(Compound 490);

1,4-Dihydro-4,4-dimethyl-6-(N-2,2,2-trifluoroethyl)amino-1,3-benzo[d]oxazin-2-one(Compound 491);

(±)-1,4-Dihydro-4-methyl-6-diallylamino-1,3-benzo[d]oxazin-2-one(Compound 492);

(±)-6-Amino-1,4-dihydro-4-methyl-1,3-benzo[d]oxazin-2-one (Compound494);

6-Amino-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound 495);

6-Diallylamino-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound497);

3,4-Dihydro-4,4-dimethyl-6-dipropylamino-2(1H)-quinolinone (Compound498);

3,4-Dihydro-4,4-dimethyl-6-propylamino-2(1H)-quinolinone (Compound 499);

3,4-Dihydro-4,4-dimethyl-6-(N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone(Compound 500);

3,4-Dihydro-4,4-dimethyl-6-(bis-N,N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone(Compound 501);

3,4-Dihydro-6-(N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone (Compound502);

6-Amino-3,4-dihydro-2(1H)-quinolinone (Compound 503);

3,4-Dihydro-6-(bis-N,N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone(Compound 505);

5-(bis-N,N-2,2,2-Trifluoroethyl)amino-3,3-spirocyclohexyl-2-indolone(Compound 506);

5-Amino-3-spirocyclohexyloxindole (Compound 507);

7-(bis-N,N-2,2,2-Trifluoroethyl)amino-1,4-benzoxazin-3(4H)-one (Compound508);

7-amino-1,4-benzoxazin-3(4H)-one (Compound 509);

6-(bis-N,N-2,2,2-Trifluoroethyl)amino-2,4-dichloroquinoline (Compound510);

6-amino-1,4-dichloro-2(1H)-quinolinone (Compound 511);

7-Amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 512);

7-Propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 513);

7-Isopropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 514);

7-(2,2-Dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 515);

7-(2-Methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound516);

7-Methylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 517);

7-Dimethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 518);

7-Benzylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 519);

7-(2,2,3,3,3-Pentafluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 520);

7-Butylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 521);

7-Ethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 522);

7-(-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 523);

7-Cyclohexylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 524);

7-Cyclopentylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 525);

7-Cyclobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 526);

7-(2-Hydroxy-2-methylpropionyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 527);

7-(Trifluoroacetamido)-4-trifluoromethyl-2(1H)-quinolinone (Compound528); 1-Methyl-7-methylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 529);

1-Methyl-7-dimethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound530);

1-Methyl-7-(N-methyl-N-isopropylamino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 531);

1-Methyl-7-(2,2,2-trifluoromethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 532);

3-Fluoro-7-(2,2,2-trifluoromethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 533);

3-Fluoro-7-amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 534);

3-Fluoro-7-isopropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound535);

3-Fluoro-7-cyclopentylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 536);

3-Fluoro-7-cyclohexylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound537);

3-Fluoro-7-cyclobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound538);

3-Fluoro-7-propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound539);

3-Fluoro-1-methyl-7-(N-methyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 540);

3-Fluoro-1-methyl-7-propylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 541);

6-Fluoro-7-amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 542);

6-Fluoro-7-propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound543);

6-Fluoro-7-isobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound544);

6-Fluoro-1-methyl-7-propylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 545);

6-Fluoro-1-methyl-7-(N-methyl-N-propylamino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 546);

7-Amino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 547);

7-Isobutylamino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound548);

7-Propylamino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound549);

7-(1,1-Dimethyl-3-oxobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 550);

7-(1,1,3-Trimethyl-3-hydroxybutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 551);

7-(1,1,3-Trimethyl-3-butenylamino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 552);

7-(1-Phenylaminocarbonylisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 553);

7-(2-Hydroxy-1,1-dimethylethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 556);

7-(N-1-Formylisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 558);

7-(1,1-Dimethylallyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound559);

7-(1,1-Dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 560);

7-(1-Methyl-1-acetylenylpropyl)amino]-4-(trifluoromethyl)-2(1H)-quinolinone(Compound 561);

7-(1-Ethyl-1-methylpropyl)amino-4-(trifluoromethyl)-2(1H)-quinolinone(Compound 562);

8-Methyl-7-(3-methyl-2-butenyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 563);

8-Methyl-7-(3-methylbutyl)amino-4-(trifluoromethyl)-2(1H)-quinolinone(Compound 566);

8-Methyl-7-propylamino-4-(trifluoromethyl)-2(1H)-quinolinone (Compound567);

8-Methyl-7-isobutylamino-4-(trifluoromethyl)-2(1H)-quinolinone (Compound569);

7-Amino-6-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-2(1H)-quinolinone(Compound 571);

7-Isobutylmino-6-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-2(1H)-quinolinone(Compound 574);

7-(2-Picolylamino)-6-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-2(1H)-quinolinone(Compound 575);

7-Amino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 576);

7-Amino-6-ethyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 577);

7-Amino-6-propyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 580);

7-Amino-6-sec-butyl4-trifluoromethyl-2(1H)-quinolinone (Compound 581);

7-Amino-6-cyclohexyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 582);

6-Ethyl-7-(2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 585);

6-Ethyl-7-methylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound586);

6-Ethyl-7-dimethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound587);

6-Isobutyl-7-methylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound588);

7-(1-Morpholino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 589);

5-Amino-7-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 592);

5-Propylamino-7-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound594);

7-Chloro-5-hydroxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 595);

5-Amino-6-bromo-3,4-dihydro-4-hydroxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 596);

6-Bromo-5-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 598);

6-(bis-N,N-2,2,2-trifluoroethyl)amino-5-methoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 600);

6-amino-5-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 601);

6-(N-2,2,2-Trifluoroethyl)amino-5-propyloxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 602);

6-amino-5-propyloxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 603);

6-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-propyloxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 604);

6-(N-2,2,2-Trifluoroethyl)amino-5-ethoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 605);

6-amino-5-ethoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 606);

6-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-ethoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 607);

6-(N-2,2,2-Trifluoroethyl)amino-5-(3,3,3-trifluoropropyloxy)-4-trifluoromethyl-2(1H)-quinolinone(Compound 608);

6-amino-5-(3,3,3-trifluoropropyloxy)-4-trifluoromethyl-2(1H)-quinolinone(Compound 609);

6-(N-2,2,2-Trifluoroethyl)amino-5-chloro-4-trifluoromethyl-2(1H)-quinolinone(Compound 610);

6-amino-5-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 611);

6-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-chloro-4-trifluoromethyl-2(1H)-quinolinone(Compound 612);

6-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 613);

6-Chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 614);

6-Isopropyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 615);

6-Cyclohexyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 616);

6-(1-trans-Propenyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound 617);

6-Cyclohexyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound618);

7-Fluoro-6-methyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 619);

5,7-Difluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 620);

6-Methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 621);

6-Hydroxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 622);

6-Benzyloxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 623);

6-(3-Pentyloxy)-4-trifluoromethyl-2(1H)-quinolinone (Compound 624);

6-(1-Hydroxy-3,3,5,5-tetramethyl)cyclohexyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 625);

6-(3,3,5,5-Tetramethyl)cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 626);

6-(5,5-Dimethycyclopentenyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 627);

6-(2,2-Dimethycyclopentyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound628);

6-(1-Hydroxycyclohexyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound629);

6-Cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 630);

6-Cyclohexyl-4-trifluoromethyl-2(1H)-thioquinolinone (Compound 631);

6-Cyclopentenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 632);

6-Cycloheptenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 633);

6-Bromo-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 634);

6-Cyclohexenyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound635);

6-Cyclohexyl-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound636);

6-Bromo-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 637);

6-Cyclopentyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound638);

(Z)-6-(1-Propyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound639);

(E)-6-(1-Propyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound640);

6-(1-Propyl)butyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 641);

(E)-6-(1-Methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound642);

(Z)-6-(1-Methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound643);

(±)-6-(1-Methyl)butyl-4-trifluoromethyl-2(1H)-quinolinone (Compound644);

(E)-6-(1-Ethyl-1-)propenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound645);

(Z)-6-(1-Ethyl-1-)propenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound646);

6-(1-Ethyl)propyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 647);

6-(1-Isopropyl-2-methyl-1-)propenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 648);

6-(1-Isopropyl-2-methyl)propyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 649);

(Z)-6-(1-Isobutyl-3-methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 650);

(E)-6-(1-Isobutyl-3-methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 651);

6-(1-Isobutyl-3-methyl)butyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 652);

6-(1-Propyl)butyl-4-trifluoromethyl-2(1H)-thioquinolinone (Compound653);

6-(3-Oxo-1-)cyclopentenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound654);

6-(3-Oxo-1-)cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound655);

6-(3-Oxo-1-)cyclopentenyl-3-methyl-4-difluoromethyl-2(1H)-quinolinone(Compound 656);

6-(3-Oxo-1-)cyclohexenyl-3-methyl-4-difluoromethyl-2(1H)-quinolinone(Compound 657);

(±)-6-(3-Hydroxy-1-)cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 658);

6-(1-Hydroxy-1,1-diphenyl)methyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 659);

6-Diphenylmethyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 660);

6-(3-hydroxy-3-methyl-1-)butynyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 661);

6-(1-Hydroxy)cyclopentyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 662);

6-Bromo-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound663);

6-(1-Cyclopentenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 664);

6-Cyclopentyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 665);

6-(1-Hydroxy)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 666);

6-(1-Cyclohexenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 667);

6-Cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound668);

6-(1-Hydroxy)cycloheptyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 669);

6-(1-Cycloheptenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 670);

6-(1-Cycloheptyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 671);

6-(2,6,6-Trimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 672);

(±)-6-(3,3,5-Trimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 673);

(±)-6-(3,5,5-Trimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 674);

(±)-6-(5-Methyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 675);

(±)-6-(3-Methyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 676);

(±)-6-(2,6-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 677);

(±)-6-(2-Bicyclo[2.2.1]heptenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 678);

(±)-6-(4,5-trans-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 679);

(±)-6-(3,4-trans-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 680);

6-(6,6-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 681);

6-(5,5-Dimethyl-1-)cyclopentenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 682);

(±)-6-(3,3,5-cis-Trimethyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 683);

(±)-6-(3,3,5-trans-Trimethyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 684);

(±)-6-(3-cis-Methyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 685);

(±)-6-(3-trans-Methyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 686);

(±)-6-(2,6-cis,cis-Dimethyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 687);

(E)-6-1,4-Dimethyl-1-)pentenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 688);

6-(1-Cyclohexenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione(Compound 689);

6-(3-Oxo-1-)cyclopentenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 690);

6-(3-Oxo-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 691);

(±)-6-(3-Hydroxy-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 692);

(±)-6-(3-cis-Hydroxy)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 693);

(±)-6-(3-Butyl-3-hydroxy-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 694);

6-(3-Oxo-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione(Compound 695);

6-Bromo-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione (Compound696);

(±)-6-(3-Hydroxy-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione(Compound 697);

(±)-6-(1-Cyclohexenyl)-1,4-dihydro-4-methyl-1,3-benzo[d]oxazin-2-one(Compound 698);

(±)-6-Bromo-1,4-dihydro-4-methyl-1,3-benzo[d]oxazin-2-one (Compound700);

6-(1-Cyclohexenyl)-1,4-dihydro-4,4,5-trimethyl-1,3-benzo[d]oxazin-2-one(Compound 701);

6-Bromo-1,4-dihydro-4,4,5-trimethyl-1,3-benzo[d]oxazin-2-one (Compound704);

6-(1-Cyclohexenyl)-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound705);

6-Bromo-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound 706);

6-Cyclohexyl-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound 707);

(±)-8-Bromo-6-(1-cyclohexenyl)-1,4-dihydro-4-trifluoromethyl-1,3-benzo[d]oxazin-2-one(Compound 708);

(±)-6,8-Dibromo-1,4-dihydro-4-trifluoromethyl-1,3-benzo[d]oxazin-2-one(Compound 711);

5-(3-Oxo-1-)cyclohexenyl-3,3-dimethyl-2-indolone (Compound 712);

5-Bromo-3,3-dimethyl-2-indolone (Compound 542);(±)-5-(3-Hydroxy-1-)cyclohexenyl-3,3-dimethyl-2-indolone (Compound 714);

(±)-5-(3-Oxocyclohexyl)-3,3-dimethyl-2-indolone (Compound 715);

(±)-5-(3-Oxocyclohexyl)-3,3-dimethyl-2-indolone (Compound 544);5-Cyclohexyl-3,3-spirocyclohexyl-2-indolone (Compound 716);

5-Bromo-3,3-spirocyclohexyl-2-indolone (Compound 717);

5-Cyclopentyl-3,3-spirocyclohexyl-2-indolone (Compound 718);

6-(1-Hydroxycyclohexyl)-2(3H)-benzothiozolone (Compound 719);

6-Cyclohexenyl-2(3H)-benzothiozolone (Compound 720);

3,4-Dihydro-6-isopropyl-3-methyl-2(1H)-quinazolinone (Compound 721);

6-Bromo-3,4-dihydro-3-methyl-2(1H)-quinazolinone (Compound 722);

1-Benzyl-6-bromo-3,4-dihydro-3-methyl-2(1H)-quinazolinone (Compound723);

1-Benzyl-6-cyclohexyl-3,4-dihydro-3-methyl-2(1H)-quinazolinone (Compound724);

6-(2,3-Difluoro)phenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound725);

4-Trifluoromethyl-6-(3-nitro)phenyl-2(1H)-quinolinone (Compound 727);

4-Trifluoromethyl-6-(3,5-dichloro)phenyl-2(1H)-quinolinone (Compound728);

4-Trifluoromethyl-6-(3-fluoro-5-N-hydroxyliminomethyl)phenyl-2(1H)-quinolinone(Compound 729);

4-Trifluoromethyl-6-(3-fluoro-5-formylmethylphenyl)-2(1H)-quinolinone(Compound 730);

4-Trifluoromethyl-6-(3-fluoro-5-cyano)phenyl-2(1H)-quinolinone (Compound731);

4-Trifluoromethyl-6-(3-fluoro-5-chloro)phenyl-2(1H)-quinolinone(Compound 732);

4-Trifluoromethyl-6-(4-hydroxymethyl)phenyl-2(1H)-quinolinone (Compound734);

4-Trifluoromethyl-6-(3-acetylphenyl)-2(1H)-quinolinone (Compound 735);

4-Trifluoromethyl-6-(4-ethylphenyl)-2(1H)-quinolinone (Compound 736);

4-Trifluoromethyl-6-(3-ethoxylphenyl)-2(1H)-quinolinone (Compound 737);

4-Trifluoromethyl-6-(3-methylphenyl)-2(1H)-quinolinone (Compound 738);

4-Trifluoromethyl-6-(3-trifluoromethylphenyl)-2(1H)-quinolinone(Compound 739);

4-Trifluoromethyl-6-(3-chlorophenyl)-2(1H)-quinolinone (Compound 740);

4-Trifluoromethyl-6-(3-fluorophenyl)-2(1H)-quinolinone (Compound 741);4-Trifluoromethyl-6-(2-methylphenyl)-2(1H)-quinolinone (Compound 742);

4-Trifluoromethyl-6-(4-formyl)phenyl-2(1H)-quinolinone (Compound 743);

4-Trifluoromethyl-6-(4-tert-butylphenyl)-2(1H)-quinolinone (Compound744);

4-Trifluoromethyl-6-(2-methoxyphenyl)-2(1H)-quinolinone (Compound 745);

4-Trifluoromethyl-6-(2-fluorophenyl)-2(1H)-quinolinone (Compound 746);

4-Trifluoromethyl-6-(4-acetylphenyl)-2(1H)-quinolinone (Compound 747);

4-Trifluoromethyl-6-(4-methylphenyl)-2(1H)-quinolinone (Compound 748);

4-Trifluoromethyl-6-(4-fluorophenyl)-2(1H)-quinolinone (Compound 749);

4-Trifluoromethyl-6-(4-methoxyphenyl)-2(1H)-quinolinone (Compound 750);

4-Trifluoromethyl-6-(3,5-bis-trifluoromethyl)phenyl-2(1H)-quinolinone(Compound 751);

4-Trifluoromethyl-6-(4-trifluoromethoxyphenyl)-2(1H)-quinolinone(Compound 752);

4-Trifluoromethyl-6-(2,4-dichlorophenyl)-2(1H)-quinolinone (Compound753);

3-Fluoro-4-trifluoromethyl-6-(2-fluorophenyl)-2(1H)-quinolinone(Compound 754);

3-Fluoro-4-trifluoromethyl-6-(2,4-dichlorophenyl)-2(1H)-quinolinone(Compound 755);

4-Trifluoromethyl-6-(4-hydroxyphenyl)-2(1H)-quinolinone (Compound 756);

6-Bromo-4-methyl-2(1H)-quinolinone (Compound 757);

4-Methyl-6-(3-methoxyphenyl)-2(1H)-quinolinone (Compound 758);

4-Methyl-6-(3B-chlorophenyl)-2(1H)-quinolinone (Compound 759);

4-Methyl-6-(3-chloro-2-methylphenyl)-2(1H)-quinolinone (Compound 760);

4-Methyl-6-(2,3-dichlorophenyl)-2(1H)-quinolinone (Compound 761);

4-Methyl-6-(2,4-dichlorophenyl)-2(1H)-quinolinone (Compound 762);

4-Methyl-6-(2-methylphenyl)-2(1H)-quinolinone (Compound 763);

4-Trifluoromethyl-6-phenyl-2(1H)-quinolinone (Compound 764);

4-Trifluoromethyl-6-propio-2(1H)-quinolinone (Compound 765);

4-Trifluoromethyl-6-(1-ethylaminopropyl)-2(1H)-quinolinone (Compound767);

4-Trifluoromethyl-6-(1-N-ethyl-N-methylaminopropyl)-2(1H)-quinolinone(Compound 768);

4-Trifluoromethyl-6-(1-hydroxy-1-methyl-2-oxopropyl)-2(1H)-quinolinone(Compound 769);

4-Trifluoromethyl-6-(4,4,4-trifluoro-1(E)-butenyl)-2(1H)-quinolinone(Compound 771);

4-Trifluoromethyl-6-(4,4,4-trifluorobutyro)-2-isopropyloxyquinoline(Compound 772);

4-Trifluoromethyl-6-(1-hydroxy-4,4,4-trifluorobutyl)-2-isopropyloxyquinoline(Compound 773);

4-Trifluoromethyl-6-(1-(3,3,3-trifluoropropyl)-1(E)-propenyl)-2(1H)-quinolinone(Compound 774);

4-Trifluoromethyl-6-(1-ethyl-1-hydroxy-4,4,4-trifluorobutyl)-2-isopropyloxyquinoline(Compound 775);

4-Trifluoromethyl-6-(1-ethyl-4,4,4-trifluoro-1(E)-butenyl)-2(1H)-quinolinone(Compound 776);

4-Trifluoromethyl-6-(1-ethyl-4,4,4-trifluoro-1(Z)-butenyl)-2(1H)-quinolinone(Compound 777);

2-Chloro-4-trifluoromethyl-6-(bis-N,N-2,2,2-trifluoroethyl)aminoquinoline(Compound 778);

2-Methoxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 779);

2-Isopropyloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 780);

2-Ethoxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 781);

2-Acetyloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 782);

2-(2-Dimethylamino)ethoxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 783);

2-Isobutyryloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 784);

2-(2,2-Dimethyl)propyryloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 785);

2-N,N-Dimethylcarbamyloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 786);

2-Cyano-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 787);

4-Trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)amino-2(1H)-quinolinoneoxime (Compound 788);

Representative PR modulator compounds (i.e., agonists and antagonists)according to the present invention include:

6-(N-Ethyl-N-2,2-dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 242);

(±)-6-(N-Propyl-N-1-methylbutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 251);

6-Cyclohexyl-4-trifluoromethyl-2(1H)-thioquinolinone (Compound 631);

6-(1-Cyclohexenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 667);

-6-(1-Cycloheptyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 671);

6-(1-Cyclohexenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione(Compound 689);

6-(3-Oxo-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione(Compound 695);

(±)-6-(3-Hydroxy-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione(Compound 697);

6-(2,3-Difluoro)phenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound725);

4-Trifluoromethyl-6-(3-nitro)phenyl-2(1H)-quinolinone (Compound 727);

4-Trifluoromethyl-6-(3-fluoro-5-cyano)phenyl-2(1H)-quinolinone (Compound731);

4-Trifluoromethyl-6-(3-acetylphenyl)-2(1H)-quinolinone (Compound 735).

The sequences of steps for several general schemes to synthesize thecompounds of the present invention are shown below. In each of theSchemes the R groups (e.g., R¹, R², etc.) correspond to the specificsubstitution patterns noted in the Examples. However, it will beunderstood by those skilled in the art that other functionalitiesdisclosed herein at the indicated positions of compounds of formulas Ithrough XXXIII also comprise potential substituents for the analogouspositions on the structures within the Schemes.

Preparation of Quinolinone Compounds from Anilines

The above reaction-sequence shows the general formulation of quinolinonecompounds which are modulators of androgen and progesterone receptors.In the above reaction sequence, an aniline compound is converted to aquinolinone compound by a Knorr cyclization with an alpha-keto estercompound. The quinolinone may then be converted to various derivativesincluding but not limited to thioquinolinones, quinolines, alkylatedquinolinones, and functionalized quinolinones. In the above scheme, Rrepresents various aromatic substituents contained on the anilinecompound known to those skilled in the art. The R group on thequinolinone compounds may be interconverted to various substituentsincluding but not limited to nitro, amino, alkylamino, halogen, alkyl,aryl, dialkylamino, pyrrole, and oxazolidene groups by various chemicalreactions known to those skilled in the art. The R′ group representsvarious aromatic subsitutents known to those skilled in the art and mayoriginate from any of the 3, 5, and 6 positions on the ring, and n maybe from 0 to 3. The R′ groups on the quinolinone compounds may also beinterconverted to various substitutents by chemistry known to thoseskilled in the art to form derivative quinolinone compounds. Schemes Ithrough VI below show various preferred embodiments of the currentinvention.

Scheme I describes a method to prepare quinolinone compounds such asStructure 5, nitro-quinolinone compounds such as Structure 6, andamino-2-quinolinone compounds such as Structure 3 through modified Knorrreactions. Thermal condensation of a 4-aminoacetanilide (Structure 1)with a 3-ketoester, for example, ethyl 4,4,4-trifluoroacetoacetate innitrobenzene affords a bis-amide such as Structure 2. When a bis-amidecompound of Structure 2 is treated with concentrated sulfuric acid at60-100° C., aminoquinolinone compounds of Structure 3 are produced. Analternate process of preparing 6-aminoquinolinone compounds such asStructure 3 starts with a similar Knorr reaction. The synthesis beginswith reaction of an aniline such as Structure 4 and a 3-ketoester inrefluxing toluene followed by treatment of a Lewis acid such asp-toluenesulfonic acid to produce a 2-quinolinone such as Structure 5.Classic nitration of the 2-quinolinone (e.g., Structure 5) selectivelyprovides a 6-nitroquinolinone compound (e.g., Structure 6). Reduction ofthe nitroquinolinone such as Structure 6 under standard reductionconditions (e.g., metal catalyzed hydrogenation or tin chloridereduction) affords aminoquinolinone compounds such as Structure 3.

Scheme II describes the N-substitution of the 6-amino-2-quinolinone suchas Structure 3 and the conversion of Structure 3 to mercapto analogues.A two-step sequential reductive alkylation of the aminoquinolinone(e.g., Structure 3) with an aldehyde or ketone or acid in the presenceof a reducing agent, such as sodium cyanoborohydride or sodiumborohydride affords compounds of Structure 7. Treatment of anamino-2-quinolinone compound (e.g., Structure 3) with an acylatingagent, such as acetyl chloride or anhydride, in the presence of a basesuch as pyridine or triethylamine provides amides or sulfonamidescompounds as shown in Structure 7. Treatment of quinolinones ofStructure 7 with Lawesson's reagent provides a correspondingthioquinolinone compound of Structure 8. Treatment of compounds ofStructure 7 with an alkylating agent such as alkyl iodide in thepresence of sodium hydride in a polar solvent, such as tetrahydrofurangives compounds of Structure 9. Direct alkylation of Structure 3provides compounds of Structure 10. The mercapto analogues of Structures12 and 13 are prepared through diazo intermediate of Structure 11.

Scheme III describes an alternate method for the syntheses of 6-aminocompounds of Structures 7, 20, 21 and 22. The process begins with astep-wise Knorr reaction, in which 4-Bromoaniline (Structure 14) and a3-ketoester such as the trifluoroacetoacetate are heated in reflux intoluene provides an amide such as Structure 15 and heating inconcentrated sulfuric acid affords 4-bromoquinolinone such as Structure16. Treatment of quinolinones such as Structure 16 with 2-iodopropane,catalyzed by cesium fluoride in DMF afford alkoxyquinoline compoundssuch as Structure 17. Palladium-catalyzed coupling reaction betweenbromoquinolines such as Structure 17 and alkylamines gives compounds ofStructures 18 and 19. Hydrolysis of the quinoline compounds (Structures18 and 19) in acidic condition provide compounds of Structures 7 and 20.Compounds of Structures 21 and 22 are prepared in a similar fashion.

Scheme IV shows additional alkylation strategies of 6-aminoquinolinoneof Structure 3 to provide 6-oxazolidine-quinolinone compounds (e.g.,Structure 25), 6-cycloalkylamino-quinolinone compounds (e.g., Structure20) and compounds of Structures 7 and 27.

The process of Scheme IV begins with reductive alkylation of anaminoquinolinone (e.g., Structure 3), with α-hydroxyketones of Structure23 in the presence of a reducing agent such as sodium cyanoborohydrideto provide compounds of Structure 24. Formation of an oxazolidinecompound such as Structure 25 is carried out by treatment of an aminolcompound such as Structure 24 with an aldehyde or its correspondinghydrate in the presence of an acid. Quinolinone compounds of Structure20 are prepared by condensation of an aminoquinolinone (e.g., Structure3) and a diketone such as Structure 23 in the presence of a reducingagent. Compounds such as Structure 7 are prepared by alkylation ofquinoline intermediate of Structure 26 derived from Structure 3 with analkyl halide. Direct alkylation of Structure 3 with halides affordsmixture compounds of Structures 7 and 27.

Scheme V shows the preparation of substituted quinolinones of Structures20a and 31 from anilines of Structure 28 or 6-aminoquinolinones such asStructure 3. The process begins with a Knorr cyclization of a meta- orortho-substituted aniline (e.g., Structure 28) with a 3-ketoester toafford compounds of Structure 29. Nitration of compounds such asStructure 29 followed by reduction of the nitro group affordspredominantly 6-amino compounds of Structure 30. Alternately compoundsof Structure 30 are also obtained by modification of 6-aminoquinolinonessuch as Structure 3. For example, bromination of compounds ofStructure-3 with NBS provides a 7-bromo-2-quinolinone compound (e.g.,Structure 30, where R³=bromo). Quinolinone compounds as shown inStructures 20a and 31 are synthesized in a similar fashion as thatdescribed in Schemes II and IV from the substituted6-amino-2-quinolinones of Structure 30.

Scheme VI describes the side-chain modification of the6-cycloamino-2-quinolinones of Structure 32. The process of Scheme VIstarts with the reduction of an ester derivative of Structure 32 to givehydroxycompounds of Structure 33. Conversion of compounds of Structure33 to tosylated analogues followed by nucleophilic substitution affordscompounds of Structure 34. Oxidation of compounds of Structure 33provides the formyl derivatives of Structure 35. Addition of anucleophile to compounds of Structure 35 gives secondary alcoholanalogues of Structure 36. Further manipulation affords compounds ofStructure 37.

Scheme VII describes Knorr reactions of substituted anilines to producefunctionalized quinolinone compounds. The process of Scheme VII startswith alkylation of an aniline compound such as Structure 38 withtrifluoroacetaldehyde in the presence of sodium cyanoborohydridefollowed by zinc reduction to provide an alkylated bis-amine compoundsuch as Structure 39. A typical Knorr procedure converts the alkylatedamine compound 39 and ethyl 4,4,4-trifluoroacetoacetate to a quinolinonecompound such as 40. Reductive alkylation of compounds of 40 provides abis-alkylaminoquinolinone such as Structure 41. Treatment of compoundsof Structure 41 with thiophenol affords 7-hydroxyquinolinone compoundssuch as 42.

Scheme VIII describes the synthesis of 6-alkylaminocoumarins, asdemonstrated by Structure 45, from phenol through a similar route asthat described in Schemes I and II. A mixture of a phenol compound and a3-ketoester such as ethyl 4,4,4-trifluoroacetoacetate are heated inrefluxing toluene in the presence of TsOH to afford a coumarin compounde.g., Structure 43. Nitration of coumarin compounds (e.g., Structure 43)followed by hydrogenation give aminocoumarin compounds such as Structure44. Sequential reductive alkylation provides dialkylamino-coumarincompounds as shown in Structure 45. Hydrogenation of adialkylamino-coumarin compound (e.g., Structure 45) affords compoundsStructure 46.

In another preferred embodiment, the syntheses of benzo-oxazinonecompounds (e.g., Structure 49) and derivatives thereof (e.g., Structures51 and 52) are shown in Scheme IX.

The process of Scheme IX begins with the treatment of an alkenylanilinecompound such as Structure 47 with chloroformate in the presence of DMAPin THF to produce carbamates such as Structure 48. Benzoxazinonecompounds such as Structure 49 (W═O) are produced by p-tolylsulfonicacid catalyzed intra-molecular cyclization of a carbamate (e.g.,Structure 48).

An alternate synthesis of benzo-oxazinone compounds of Structure 49 isalso shown in Scheme IX. In this synthetic route, carbon nucleophilesare added to 2-aminobenzoic acid to give the amino-alcohol compound 50,which is converted to an aminobenzo-oxazinone compound such as Structure49 by either 1,1′-carbonyldiimidazole in THF or thecarbonate-cyclization route as described above. A classic nitrationreaction of the aromatic benzoxazinone compound by nitric acid inconcentrate sulfuric acid followed by palladium catalyzed hydrogenationproduces amino compounds such as Structure 51. A two-step sequentialreductive alkylation as described previously producesdialkylamine-benzoxazinone compounds as shown in Structure 52.

In another preferred embodiment, bioisosteres of 6-amino-2-quinolinonessuch as 5-amino-oxinole, 6-amino-benzoxazinone and quinoline compounds,which are useful AR and PR modulators, are prepared from a correspondingbicyclic compound. The bicyclic compounds such as Structures 53, 56 and58 are prepared by synthetic methods known to those skilled in the art.

Scheme X describes a synthetic process for preparing5-bisalkylamino-oxindole compounds such as Structure 55 and6-bisalkylated compounds of Structures 57 and 59. The method forpreparing these compounds is described in Scheme IX and is analogous tothe preparation of compounds such as Structure 52 from the correspondingquinolinone compound. The process involves sequential nitration,reduction and/or alkylation of the amine to produce compounds ofStructures 55, 57 and 59.

Scheme XI describes a preferred synthetic method to prepare7-alkylamino-2-quinolinones such as Structure 63 via the Knorr reactionas previously described. The process of Scheme XI begins with a modifiedKnorr cyclization of 1,3-phenylenediamines of Structure 60 to give a7-aminoquinolinone compound such as Structure 61. A sequential reductivealkylation of Structure 61 in a similar process as that described inScheme II affords compounds such as Structure 62. Alkylation ofquinolinone such as 62 with alkyl iodide in the presence of sodiumhydride generates 1-alkyl quinolinone compounds such as Structure 63.

In another preferred aspect of the invention, alkylamino-quinolinonecompounds (e.g., Structure 66) are prepared from a correspondingamino-quinolinone compound. Schemes XII, XIII and XIV describe themethods of introducing a quaternary carbon next to the amino position.

The process of Scheme XII begins with the treatment of a7-aminoquinolinone such as Structure 61a with acetic acid in acetone toafford an alkyl amino-quinolinone compound such as Structure 64.Methyllithium addition to a compound such as Structure 64 in THFprovides the corresponding alcohol adduct e.g., Structure 65. An acidcatalyzed dehydration of an amino alcohol compound such as 65 gives analkene amino-quinolinone compound such as 66.

In another preferred reaction sequence, alkyl-quinolinones are producedby a Knorr cyclization of a diamine compound as previously described.Subsequent alkylation and oxidation produces alkyl-quinolinonecompounds. The alkylamine-quinolinones may then be further converted tovarious derivative compounds by reactions known to those skilled in theart as exemplified in the examples below.

Scheme XIII describes an alternate procedure to synthesize2-quinolinones with a quaternary carbon adjacent to the 7-nitrogen. Theprocess of Scheme XIII begins with a typical Knorr cyclization of a1,3-phenylenediamine with a α-ketoester, ethyl4,4,4-trifluoroacetoacetate, to afford an aminoquinoline compound suchas 67 as a minor product. Alkylation of an aminoquinoline compound suchas 67 with an amide such as N-phenyl-α-bromoisobutyramide in thepresence of sodium hydride affords an alkylated quinoline product suchas 68 in good yield. Hydrolysis of an alkylated quinoline compound(e.g., Structure 68) with HI provides a 2-quinolinone such as 69.Methylation of an alkylated quinoline compound such as 68 withiodomethane in the presence of sodium hydride followed by HI mediatedhydrolysis produces a quinolinone such as Structure 70. Reduction of anamide compound such as 70 with DIBAL-H affords an aldehyde compound suchas 71 and an alcohol product such as 72. Wittig reaction of aldehydessuch as 71 affords olefins such as Structure 73. Hydrogenation of anallylamino-quinolinone compound such as Structure 73 produces acorresponding alkylamino-quinolinone compound as shown in Structure 74.

In another preferred aspect of the invention, alkylamino-quinolinonecompounds are produced by copper chloride catalyzed substitution of anamino-quinolinone compound. Scheme XIV describes an alternateN-alkylation method for the preparation of alkylamino-quinolinonecompounds. Treatment of an amino quinolinone compound such as 61a andpropargyl acetate with copper chloride and a base such as triethylaminein THF affords alkylamine-quinolinone products such as 75. Hydrogenationof an amino-acetylene compound such as 75 provides an alkylaminoquinolinone compound as shown in Structure 76 in excellent yield.

Alkyl-diamino compounds (e.g. Structure 78) are produced by twoalternate synthetic methods in another preferred synthetic route asshown in Scheme XV. Alkylations of amino compounds as shown below arereactions known to those skilled in the art. The reaction as shown belowis as an example of the preparation of these types of compounds.

The process of Scheme XV begins with alkylation of a mono-protected1,3-phenylenediamine followed by trifluoroacetic acid (TFA) mediatedde-protection to produce diamino compounds such as Structure 78.Alternately, alkylation of a 3-nitroaniline followed by a reduction ofthe nitro group generates the same intermediates of Structure 78. Knorrcyclization as previously described in the presence of a α-keto-estersuch as ethyl 4,4,4-trifluoroacetoacetate affords compounds such asStructure 79 in good yield.

Substituted diamino compounds are produced in another preferredembodiment of the invention. The diamino compounds are then furtherreacted to produce quinolinone compounds via the Knorr reaction aspreviously described. Scheme XVI describes a synthetic process forproducing alkoxy-alkylamino-quinolinone compounds such as Structure 84.

The process starts with substitution of a bis-nitrofluorobenzene with2,2,2-trifluoroethyanol in the presence of a base, such as sodiumhydride to provide an alkoxy-nitrobenzene compound such as Structure 81.Conversion of bis-nitro groups to bis-amino groups is accomplished byhydrogenation or metal reduction to give aniline compounds such asStructure 82. A standard Knorr reaction with ethyl4,4,4-trifluoroacetoacetate and p-tolylsufonic acid affordsalkoxy-quinolinones such as Structure 83 in high yield. Analkoxy-amino-quinolinone compound such as 83 may subsequently bealkylated as previously described. For example, reductive alkylation ofa compound such as Structure 83 with an aldehyde and sodiumcyanoborohydride gives alkoxy-alkylamino-quinolinone compounds as shownin Structure 84.

In another preferred reaction, substituted diamine compounds (e.g.,Structure 87) are produced by electrophilic aromatic substitution ofactivated aromatic amino-benzene rings. The substituted diaminecompounds are then further reacted to produce quinolinone compounds(e.g., Structure 88) and subsequent quinolinone derivatives thereof(e.g., Structure 89) as previously described. Quinolinone compounds asshown in Scheme XVII are useful PR and AR modulators as describedherein.

Scheme XVII describes processes to synthesize substitutedalkylaminoquinolinone compounds such as 89. Treatment ofortho-substituted aniline such as Structure 85 or a 4-substitutedaniline such as 90 with nitric acid in concentrated sulfuric acidgenerates meta-nitrated products such as 86 or 91 in high yield.Hydrogenation of the nitro group on compounds such as 86 or 91 providesthe Knorr precursors as shown as Structure 87. Treatment of1,3-phenylenediamines such as 87 with ethyl 4,4,4-trifluoroacetoacetatein refluxing toluene in the presence of a catalytic amount of acid, suchas p-tolylsufonic acid, affords quinolinone compounds as shown inStructure 88. Additional alkylation at the 7-amino group provides morefunctionalized compounds such as Structure 89 as previously described.

In a preferred aspect of the invention, functionalized quinolinones orfunctionalized dihydro-quinolinones are prepared from the correspondingsubstituted diamino-benzene compound (e.g. Structure 92). The aminoportion of the quinolinone and dihydro-quinolinone compounds (e.g.Structures 94 and 93), may then be converted to other functional groupsby chemical reactions known to those skilled in the art. Examples ofsuch conversions are demonstrated in Scheme XVIII, for example in thepreparation of compounds such as 95, 96, 97 and 100.

Scheme XVIII above describes methods of preparing functionalizedquinolinones. The process of Scheme XVIII begins with modified Knorrreactions of diamine 92 with ethyl 4,4,4-trifluoroacetoacetate. In thep-tolylsufonic acid catalyzed refluxing toluene condition quinolinonecompounds such as 94 are major products. In an alternate synthesis, thereaction is carried out in refluxing ethanol, which produces compoundssuch as Structure 93 as major products. Compounds such as 93 may then beconverted to quinolinones such as 94 by acid catalyzed dehydration. The5-amino group of compounds 93 or 94 is converted to 5-hydroxyderivatives of Structure 95 by diazotization-hydrolysis conditions usingsodium nitrite and sulfuric acid. A similar condition by sodium nitriteand chloride converts the 5-amino to 5-chloro derivatives of Structure98. Reductive alkylation of compounds of Structures 94 and 99 affordscompounds of Structures 96 and 100.

Another synthetic route into functionalized quinolinone compounds (e.g.Structures 102 and 104) is shown in Scheme XIX. Scheme XIX describes thesynthesis of substituted quinolinone compounds such as Structures 102and 104 under similar Knorr reaction conditions as that described inScheme 1. The Knorr reaction may also be used on substituted anilinecompounds (e.g. Structure 101) to produce functionalized quinolinonecompounds such as Structure 102. The functionalized quinolinonecompounds as shown above may then be converted to other functionalgroups to produce additional quinolinone derivatives such as compoundsof Structure 104 as described herein.

Alkylated Aryl Compounds from Arylhalogens and Ketones

In another aspect of the invention, halogenated quinolinones,benzo-oxazinones, indolones, benzothiozolones, and quinazolinones (i.e.,arylhalogen compounds) produce alkylated derivatives by a C—C couplingof the arylhalogen carbon and a ketone with a lithium reagent. The abovereaction sequence depicts the conversion of arylhalogen compounds toarylalkyl compounds by reaction of the aryl halide compound with aketone. Schemes XX through XXIX depict further examples of this type offunctional group conversion and are provided to further illustrate thereaction with various ketones and aryl compounds.

In another aspect of the invention, functionalized quinolinone compounds(e.g., Structure 105 and 109) are produced by a C—C coupling of ahalo-quinolinone such as Structure 16a and a ketone as shown in SchemesXX and XXI. The halo-quinolinone may be produced by either of twosynthetic routes as shown below in Scheme XX. Scheme XX describes thesynthesis of a number of functionalized quinolinone compounds.

3-Fluorinated-quinolinone compounds such as Structure 16a may be formedby treatment of a 3-ketoamide 15 with a fluorination reagent, such asfluorobenzenesulfonimide, to provide a fluorinated derivative productsuch as Structure 15a, which is converted to the 3-fluoro quinolinonecompound 16a (R=fluorine) by the Knorr cyclization with concentratedsulfuric acid.

A 7-methoxy analogue of Structure 16a is prepared by NBS bromination ofquinolinone 29a. Addition of a dianion generated from abromo-quinolinone such as 16a by two equivalents of base, such asalkyllithium, to a ketone affords the tertiary alcohols as shown inStructure 105. Dehydration of an alcohol such as 105 with a catalyticamount of acid, such as sulfuric acid, gives olefins of Structure 106.Subsequent hydrogenation of olefins such as 106 provides analkyl-quinolinone such as Structure 107. A thioquinolinone derivativemay be synthesized by treatment of compounds 107 with Lawesson's reagentin toluene as previously described.

Scheme XXI describes a process of preparing alkenyl-quinolinonecompounds. Addition of the dianion generated from a bromoquinolinonesuch as 16b by methyllithium and n-butyllithium to a protected cyclic1,3-diketone affords oxo-alkenyl-quinolinone compounds such as Structure109 upon acid mediated hydrolysis of the adducts. Reduction of the oxogroup on a compound such as 109 with DIBAH provides the alcoholderivative as shown in Structure 110.

A further example of the conversion of arylhalogen compounds (e.g.Structure 16) to arylalkyl compounds is shown in Scheme XXII. SchemeXXII describes the preparation of additional 6-alkyl 2-quinolinonecompounds from the quinolinone dianion in a preferred aspect of theinvention. Addition of a dianion generated from a bromo quinolinone,methyllithium and n-butyllithium to benzophenone gives an alkylquinolinone such as compound 111. Reduction of compound 111 withtriethylsilane in the presence of an acid catalyst, such as TFA, affordsan alkyl-quinolinone compound such as 112.

In a further embodiment of the invention, aryl halogen compounds areconverted to aryl alkynes by a palladium catalyzed coupling reactionbetween the aryl halogen (e.g., Structure 16) and a terminal alkyne asshown above in Scheme XXII. For example, a palladium(II) catalyzedreaction of a bromoquinolinone such as 16 and a terminal alkyne such asdimethyl propargyl alcohol provides an alkynyl-quinolinone compound suchas 113.

A method of converting arylhalides to arylalkyl compounds is alsoemployed with benzo-oxazinone compounds as shown in the above example.Scheme XXIII describes methods of synthesizing alkyl1,3-benzo[d]oxazin-2-one compounds.

The process of Scheme XXIII begins with a bromination of a compound suchas 49a with bromine to give a bromobenzo-oxazinone compound such as 114.Addition of the dianion generated from the lithiation of a compound suchas 49a to a ketone provides the hydroxy-alkyl adducts of Structure 115.Dehydration of alcohol derivative 115 with a catalytic amount ofsulfuric acid affords compounds such as Structure 116, which may behydrogenated to give compounds such as Structure 118. Benzothiooxazinonecompounds as shown in Structure 117 are prepared from the correspondingcarbonyl compound (e.g., such as Structure 116) by treatment withLawesson's reagent as previously described.

Scheme XXIV describes additional methods to prepare alkylbenzo-oxazinones. The process of Scheme XXIV begins with addition of thedianion generated from lithiation of compound 114 by alkyllithium to aprotected 1,3-cyclodiketone. Hydrolysis of adducts with an acid affordsalkene compounds Structure 119. Addition of n-butyllithium to an enonesuch as 119 provides a tertiary alcohol such as 122. Reduction of theenone 119 with DIBAL-H gives a secondary alcohol such as 120.Hydrogenation affords compound such as 121. Alkyl thio-benzo-oxazinonecompounds are prepared by a similar process but using athiobenzo-oxazinone 10 such as 118a in place of the oxo compound.

In another preferred aspect of the invention, substitutedbenzo-oxazinone compounds (e.g., Structure 125) are prepared for anamino-benzoic acid and an organometallic reagent to form ahydroxy-aniline compound (e.g., Structure 124) with either a halide orcarbonyl diimidazole to form a benzo-oxazinone. The process of SchemeXXV begins with addition of either alkyl lithium or a Grignard reagentto a 2-aminobenzoic acid such as Structure 123 to generate amino alcoholcompound such as Structure 124. A previously described cyclizationprocedure from either 1,1′-carbonyldiimidazole treatment or acidcatalyzed carbamate intermediate affords compounds such as Structure125. Treatment of benzo-oxazinone compounds (e.g., Structure 125) withbromine provides brominated benzo-oxazinone compounds such as Structure126. Addition of an anion generated from compounds such as 126 and analkyl lithium reagent to a ketone such as cyclohexanone affordscompounds such as Structure 127. The alkenyl-benzo-oxazinone compound(e.g., 127) may be hydrogenated to give alkyl compounds such asStructure 128.

Scheme XXVI describes a process to introduce a trifluoromethyl group atthe 4-position of benzo-oxazinone compounds. The process starts withaddition of an N-protected 2-aminoaryl lithium generated by metalhalogen exchange of 2-aminobromobenzene and n-butyllithium to ethyltrifluoroacetate followed by a reduction with sodium borohydride toprovide compounds such as 129. Acid catalyzed cyclization of compoundssuch as 129 afford benzo-oxazinone compounds such as 130. Thebenzo-oxazinone compound may subsequently be treated with bromine togenerate a bis-brominated product such as 131. As previously described,the bromine may be substituted with an alkyl group. For example, the6-cyclohexenyl derivative 132 is prepared in a similar fashion as thatdescribed in Scheme XXV.

Scheme XXVII describes methods to prepare alkyl oxindole derivatives bybromination of the oxindole followed by substitution of the brominegroup with an alkyl group as previously described. The process startswith alkylation of 2-indolone with alkyl halides in the presence ofn-butyllithium followed by selective bromination to afford brominatedoxindole compounds (e.g., Structure 133). The alkyl-indolone compoundsare prepared from a bromo compound such as 133 by a procedure similar tothat as described in Scheme XXV.

Scheme XXVIII describes a synthetic route of producingalkyl-benzothiozolones. The process is similar to that as described inScheme XXV but using a halogenated benzothiozolone compound.

Scheme XXIX describes a process to prepare 2-quinazolinones. The processof Scheme XXIX begins with bromination of compound 140 to affordcompound 141, which is derivatized by treatment with benzyl bromide inthe presence of sodium hydride to give compound 142. A palladiumcatalyzed aromatic substitution of compounds of Structure 141 or 142 byGrignard reagents provides compounds of Structure 143.

Scheme XXX describes an alternate method of preparing aryl-quinolinonesby a modified Suzuki coupling reaction. The process starts withpalladium catalyzed biaryl coupling of a bromo compound such asStructure 16c, a brominated quinolinone, with an aryl boronic acid(e.g., Structure 144). Aryl compounds such as Structure 145 are producedin this manner. The boronic acids of Structure 144 come from commercialsources or may be generated from aryl bromides by a standard three-stepprocedure which includes metal halogen exchange, addition to methylborate and acidic work-up. Aryl substituted compounds of the presentinvention (e.g., Structure 145) may be further functionalized bymodification of the substituents on the aryl group by standard syntheticmethods known to those skilled in the art. Alternately, aryl substitutedcompounds of the present invention such as Structure 145 may be preparedfrom the aryl aniline (e.g., 6-arylaniline, Structure 147) as shownabove by a Knorr reaction procedure as previously described.

Scheme XXXI describes additional methods to prepare 6-substituted2-quinolinones such as Structures 149, 150, 152 and 153. Lithiation ofStructure 17 followed by addition to a Weinreb's amide afford compoundsof Structure 148. Hydrolysis of quinolines such as Structure 148provides compounds of Structure 149. Compounds of Structure 150 areobtained by reductive amination of compounds such as Structure 149.Addition of a nucleophile to quinoline ketones of Structure 148generates alcohols of Structure 151, which are treated with acid toafford compounds of Structures 152 and 153.

Scheme XXXII describes the conversion of 2-quinolinones of Structure 7to 2-substituted quinoline such as Structures 154, 155 and 156 by thechemical transformations known to those skilled in the art.

Scheme XXXIII describes methods to prepare compounds with a diazocontaining side chain. Treatment of 6-aminoquinolinones such asStructure 7a with NaNO₂ affords compounds of Structure 157. Reduction ofnitroso compounds such as Structure 157 followed by alkylation provideanalogues of Structure 158. Alkylation or acylation of hydrazine such asStructure 159 generates compounds of Structures 160 and 161.

The compounds of the present invention also include racemates,stereoisomers and mixtures of said compounds, including isotopicallylabeled and radio-labeled compounds. Such isomers can be isolated bystandard resolution techniques, including fractional crystallization andchiral column chromatography.

As noted above, any of the steroid modulator compounds of the presentinvention can be combined in a mixture with a pharmaceuticallyacceptable carrier to provide pharmaceutical compositions useful fortreating the biological conditions or disorders noted herein inmammalian, and more preferably, in human patients. The particularcarrier employed in these pharmaceutical compositions may take a widevariety of forms depending upon the type of administration desired,e.g., intravenous, oral, topical, suppository or parenteral.

In preparing the compositions in oral liquid dosage forms (e.g.,suspensions, elixirs and solutions), typical pharmaceutical media, suchas water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like can be employed. Similarly, when preparingoral solid dosage forms (e.g., powders, tablets and capsules), carrierssuch as starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like will be employed. Due totheir ease of administration, tablets and capsules represent the mostadvantageous oral dosage form for the pharmaceutical compositions of thepresent invention.

For parenteral administration, the carrier will typically comprisesterile water, although other ingredients that aid in solubility orserve as preservatives, may also be included. Furthermore, injectablesuspensions may also be prepared, in which case appropriate liquidcarriers, suspending agents and the like will be employed.

For topical administration, the compounds of the present invention maybe formulated using bland, moisturizing bases, such as ointments orcreams. Examples of suitable ointment bases are petrolatum, petrolatumplus volatile silicones, lanolin, and water in oil emulsions such asEucerin™ (Beiersdorf). Examples of suitable cream bases are Nivea™ Cream(Beiersdorf), cold cream (USP), Purpose Cream™ (Johnson & Johnson),hydrophilic ointment (USP), and Lubriderm™ (Warner-Lambert).

The pharmaceutical compositions and compounds of the present inventionwill generally be administered in the form of a dosage unit (e.g.,tablet, capsule etc.) at from about 1 μg/kg of body weight to about 500mg/kg of body weight, more preferably from about 10 μg/kg to about 100mg/kg, and most preferably from about 20 μg/kg to about 20 mg/kg. Asrecognized by those skilled in the art, the particular quantity ofpharmaceutical composition according to the present inventionadministered to a patient will depend upon a number of factors,including, without limitation, the biological activity desired, thecondition of the patient, and tolerance for the drug.

The compounds of this invention also have utility when radio- orisotopically-labeled as ligands for use in assays to determine thepresence of AR or PR in a cell background or extract. They areparticularly useful due to their ability to selectively activateandrogen receptors or progesterone receptors, and can therefore be usedto determine the presence of such receptors in the presence of othersteroid receptors or related intracellular receptors.

Due to the selective specificity of the compounds of this invention forsteroid receptors, these compounds can be used to purify samples ofsteroid receptors in vitro. Such purification can be carried out bymixing samples containing steroid receptors with one or more of thecompounds of the present invention so that the compounds bind to thereceptors of choice, and then separating out the bound ligand/receptorcombination by separation techniques which are known to those of skillin the art. These techniques include column separation, filtration,centrifugation, tagging and physical separation, and antibodycomplexing, among others.

The compounds and pharmaceutical compositions of the present inventioncan advantageously be used in the treatment of the diseases andconditions described herein. In this regard, the compounds andcompositions of the present invention will prove particularly useful asmodulators of male sex steroid-dependent diseases and conditions such asthe treatment of acne, male-pattern baldness, male hormone replacementtherapy, wasting diseases, hirsutism, stimulation of hematopoiesis,hypogonadism, prostatic hyperplasia, osteoporosis (agonist), malecontraception (agonist), impotence (agonist), cancer cachexia (agonist)various hormone-dependent cancers, including, without limitation,prostate and breast cancer and as anabolic agents.

The compounds and pharmaceutical compositions of the present inventionpossess a number of advantages over previously identified steroidal andnon-steroidal compounds.

Furthermore, the compounds and pharmaceutical compositions of thepresent invention possess a number of advantages over previouslyidentified steroid modulator compounds. For example, the compounds areextremely potent activators of AR, preferably displaying 50% maximalactivation of AR at a concentration of less than 100 nM, more preferablyat a concentration of less than 50 nM, more preferably yet at aconcentration of less than 20 nM, and most preferably at a concentrationof 10 mM or less. Also, the selective compounds of the present inventiongenerally do not display undesired cross-reactivity with other steroidreceptors, as is seen with the compound mifepristone (RU486; RousselUclaf), a known PR antagonist that displays an undesirable crossreactivity on GR and AR, thereby limiting its use in long-term, chronicadministration. In addition, the compounds of the present invention, assmall organic molecules, are easier to synthesize, provide greaterstability and can be more easily administered in oral dosage forms thanother known steroidal compounds.

The invention will be further illustrated by reference to the followingnon-limiting Examples.

EXAMPLE 1 6-Amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 200,Structure 3 of Scheme I)

N-(4-Acetylaminophenyl)-4,4,4-trifluoroacetoacetylamide Hydrate(Compound 201, Structure 2 of Scheme I):

In a 100 mL round bottom flask fitted with a reflux condenser, a mixtureof 4-aminoacetanilide (Structure 1 of Scheme I) (7.5 g, 50 mmol), ethyl4,4,4-trifluoroacetoacetate (17 g, 95 mmol, 1.9 equiv), nitrobenzene (30mL), and water (2 mL, 0.11 mol) was heated in an oil bath at 130° C. for1 h, then water (1 mL) was added and the mixture was heated at 130° C.for 2 h. After cooling to room temperature Et₂O (30 mL) was added to thesolid mass and the solids were filtered and washed with Et₂O (3×30 mL),and dried under vacuum at 120° C. to give 12 g (85%) of Compound 201 asa ray crystalline solid.

6-Amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 200, Structure 3of Scheme I):

To a 50 mL r.b. flask charged with Compound 201 (3.6 g, 12 mmol) wasadded conc. H₂SO₄ (20 mL) and the dark brown mixture was heated in anoil bath at 95° C. for 16 h. After cooling to room temperature the darkpurple solution was poured onto crushed ice (50 g) and brought to pH˜2with conc. NaOH. EtOAc (50 mL) was added and the layers separated. Thewater layer was extracted with EtOAc (9×30 mL). The combined organiclayers were washed with water and brine and dried over MgSO₄. Removal ofsolvent afforded 1.2 g of a bright yellow solid, which was purified byflash chromatography (silica gel, hexane:EtOAc 2:1 to 1:2 gradient) togive Compound 200 as a bright yellow solid (0.52 g, 18%): ¹H NMR (500MHz, acetone-d₆) 10.9 (bs, 1H), 7.31 (d, J=9.3, 1H), 7.10 (dd, J=9.3,2.4, 1H), 7.04 (t, J=2.4, 1H), 6.85 (s, 1H), 4.91 (bs, 2H).

6-Amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 200, Structure 3of Scheme I) was also prepared by the following General Procedures I-IIIfrom aniline:

4-Trifluoromethyl-2(1H)-quinolinone (Compound 202, Structure 5 of SchemeI):

General Procedure I (Synthesis of 2(1H)-Quinolinone from Aniline):

A solution of aniline in benzene or toluene (2-10 mL/mmol) and anacetoacetate derivative (1.2 equiv) was heated at reflux for 12-48 hrs.The resulting.mixture was cooled to room temperature and concentratedunder reduced pressure. The crude reaction mixture was diluted inconcentrated sulfuric acid (8 mL/mmol) and heated to 80-100° C. for 6-16hrs. The resulting mixture was poured over ice and neutralized with 6 MNaOH solution to pH 7.0, extracted with CH₂Cl₂ (3×30 mL/mmol), washedwith pH 7 phosphate buffer (50 mL/mmol) and brine (50 mL/mmol). Theorganic solution was dried (MgSO₄) and concentrated under reducedpressure. Purification was performed either by flash chromatography(silica gel, 20:1, CH₂Cl₂/MeOH) or by crystallization to afford thedesired quinolinone as a fluorescent-yellow solid.

Alternatively, a mixture of aniline and a 3-ketoester such as ethyl4,4,4-trifluoroacetoacetate (1.2 equiv) in toluene (0.1-0.5 M) washeated at reflux for 24 h until the starting material was completelyconsumed by TLC. A catalytic amount of p-tolylsulfonic acid (1-10%) wasadded and the mixture was refluxed for additional 24 h. Similar work-upas described above afforded Compound 202 as a yellow solid: ¹H NMR (400MHz, acetone-d₆) 11.25 (bs, 1H),7.70 (d, J=8.0, 1H), 7.65 (t, J=8.0,1H), 7.44 (d, J=8.0, 1H), 7.32 (t, J=8.0, 1H), 6.99 (s, 1H).

6-Nitro-4-trifluoromethyl-2(1H)-quinolinone (Compound 203, Structure 6of Scheme I):

General Procedure II (Nitration Reaction):

To solution of a 2(1H)-quinolinone, such as Compound 202, in conc. H₂SO₄(0.2-1.0 M) at room temperature was added HNO₃ (1.0 equiv). The reactionmixture was stirred for 10 min and was poured into ice water. Themixture was neutralized to PH˜7 and extracted with EtOAc.Recystallization provided Compound 203 as a yellow solid: ¹H NMR (500MHz, acetone-d₆) 12.82 (bs, 1H), 8.47 (dd, J=9.5, 2.5, 1H), 8.44 (m,1H), 7.59 (d, J=9.5, 1H), 7.21 (s, 1H).

6-Amino-4-trifluoromethyl-2(1H)-quinolinone (Compound 200, Structure 3of Scheme I)

General Procedure III (Hydrogenation Reaction):

Compound 203 in EtOAc (0.2-1.0 M) was hydrogenated with a hydrogenballoon in the presence of 5% or 10% Pd/C (1-5 mol %). Filtration fromthe catalyst on Celite afforded Compound 200 as yellow solid.

EXAMPLE 2 6-Propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound204, Structure 7 of Scheme II, Where R¹=H, R²=Propyl)

This compound was prepared from Compound 200 and propionaldehyde by thefollowing General Procedure IV (Reductive alkylation of amine byaldehyde):

To a solution of Compound 200 (Structure 3 of Scheme II) (35 mg, 0.15mmol) in methanol (20 mL) was added a propionaldehyde (2-5 equiv)followed by NaCNBH₃ (2-5 equiv). The mixture was stirred at roomtemperature for 4 h and water (20 mL) was added. The water layer wasextracted with EtOAc (2×20 mL) and the combined organic layers werewashed with brine and dried over MgSO₄. Concentration and purificationby flash chromatography (silica gel, hex/EtOAc 3:1) afforded Compound204 as a yellow solid (70-95%): ¹H NMR (500 MHz, CDCl₃) 11.2 (bs, 1H),7.22 (d, J=8.8, 1H), 7.05 (s, 1H), 6.96 (dd, J=8.8, 2.4, 1H), 6.88 (s,1H), 3.77 (t, J=4.4, 1H), 3.12 (dt, J=7.5, 4.4, 2H), 1.72-1.63 (m, 2H),1.04 (t, J=7.3, 3H).

EXAMPLE 3 6-Isopropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound205, Structure 7 of Scheme II, Where R¹=H, R²=Isopropyl)

This compound was prepared from Compound 200 and acetone by thefollowing General Procedure V (Reductive alkylation of amine by ketone):

To a solution of Compound 200 (Structure 3 of Scheme II) (35 mg, 0.15mmol) in 10 mL MeOH was added acetone (0.5 mL, excess) followed byNaCNBH₃ (30 mg, 0.50 mmol) and AcOH (0.5 mL). The mixture was stirred atroom temperature for 1 h and 10 mL water was added. The water layer wasextracted with EtOAc (2×15 mL) and the combined organic layers werewashed with brine and dried over MgSO₄. Concentration and purificationby flash chromatography (silica gel, hex/EtOAc 2:1) afforded 33 mg (81%)of Compound 205 as a bright yellow solid: ¹H NMR (500 MHz, acetone-d₆)10.9 (bs, 1H), 7.33 (d, J=8.8, 1H), 7.08 (dd, J=8.8, 2.4, 1H), 6.87 (t,J=2.4, 1H), 6.86 (s, 1H), 5.00 (d, J=6.8, 1H), 3.70-3.63 (m, 1H), 1.23(d, J=6.9, 6H).

EXAMPLE 4 6-Isobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound206, Structure 7 of Scheme II, Where R¹=H, R²=Isobutyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using isobutyraldehyde in place ofpropionaldehyde. Compound 206 was isolated as a yellow solid: ¹H NMR(500 MHz, CDCl₃) 11.1 (bs, 1H), 7.20 (d, J=8.8, 1H), 7.04 (s, 1H), 6.95(dd, J=8.8, 2.4, 1H), 6.87 (s, 1H), 3.83 (bs, 1H), 2.97 (t, J=6.3, 1H),1.95-1.89 (m, 1H), 1.02 (d, J=6.8, 6H).

EXAMPLE 5 6-(2,2-Dimethylpropyl)amino-4-trifluoromethyl-2(1)-quinolinone(Compound 207, Structure 7 of Scheme II, Where R¹=H,R²=2,2-Dimethylpropyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using trimethylacetaldehyde in placeof propionaldehyde. Compound 207 was isolated as a yellow solid: ¹H NMR(500 MHz, CDCl₃) 10.4 (bs, 1H), 7.14 (d, J=8.8, 1H), 7.03 (s, 1H), 6.97(dd, J=8.8, 2.4, 1H), 6.90 (s, 1H), 3.79 (t, J=5.9, 1H), 2.94 (d, J=5.9,2H), 1.03 (s, 9H).

EXAMPLE 6 6-Cyclopentylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 208, Structure 7 of Scheme II, Where R¹=H, R²=Cyclopentyl)

This compound was prepared in a similar fashion as that described inExample 3, General Procedure V but using cyclopentanone in place ofacetone. Compound 208 was isolated as a yellow solid: ¹H NMR (500 MHz,acetone-d₆) 10.9 (bs, 1H), 7.32 (d, J=8.8, 1H), 7.08 (dd, J=8.8, 2.4,1H), 6.87 (t, J=2.4, 1H), 6.85 (s, 1H), 5.21 (d, J=6.4, 1H), 3.84-3.81(m, 1H), 2.04-2.00 (m, 2H) 1.76-1.71 (m, 2H), 1.67-1.59 (m, 2H),1.58-1.52 (m, 2H).

EXAMPLE 76-(2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 209, Structure 7 of Scheme II, Where R¹=H,R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using trifluoroacetaldehyde in placeof propionaldehyde. Compound 209 was isolated as a yellow solid: ¹H NMR(400 MHz, CDCl₃) 11.05 (s, 1H), 7.36 (d, J=8.7, 1H), 7.09 (s, 1H), 7.04(d, J=8.7, 1H), 7.02 (s, 1H), 4.10 (t, J=6.9, 1H), 3.86-3.78 (m, 2H).

EXAMPLE 86-(2,2,3,3,3-Pentafluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 210, Structure 7 of Scheme II, Where R¹=H,R²=2,2,3,3,3-Pentafluoropropyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using pentafluoropropyraldehyde inplace of propionaldehyde. Compound 210 was isolated as a yellow solid:¹H NMR (500 MHz, CDCl₃) 12.2 (bs, 1H), 7.35 (d, J=8.8, 1H), 7.09 (s,1H), 7.05 (dd, J=8.8, 2.4, 1H), 7.03 (s, 1H), 4.05 (t, J=6.8, 1H),3.91-3.84 (m, 2H).

EXAMPLE 9 6-(2,2-Difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 211, Structure 7 of Scheme II, Where R¹=H,R²=2,2-Difluoroethyl)

This compound was prepared from Compound 200 and difluoroacetic acid bythe following General Procedure VI (Reductive alkylation of amine byacid):

To a solution of an aniline such as Compound 200 (Structure 3 of SchemeII) in an acid such as difluoroacetic acid as solvent was added sodiumborohydride (excess) slowly, the resulting mixture was stirred at roomtemperature for several hours until the reaction went completion by TLC(addition of additional sodium borohydride or at elevate temperaturewould result in the formation of bis-alkylated product). The reactionwas quenched by 10% NaOH and extracted with EtOAc (2×). Removal ofsolvent and chromatography of the crude residue afforded the N-alkylatedproduct.

Compound 211 was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃)7.37 (d, J=8.8, 1H), 7.09 (s, 1H), 7.03 (dd, J=2.5, 8.9, 1H), 6.97 (s,1H), 5.97 (tt, J=3:9, 55.8, 1H), 4.03 (t, J=6.8, 1H), 3.65-3.55 (m, 2H).

EXAMPLE 106-(2-Chloro-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 212, Structure 7 of Scheme II, Where R¹=H,R²=2-Chloro-2,2-difluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using chlorodifluoroacetic acid inplace of difluoroacetic acid. Compound 212 was isolated as a yellowsolid: ¹H NMR (400 MHz, CDCl₃) 7.38 (d, J=8.7, 1H), 7.09 (s, 1H),7.08-7.05 (m, 2H), 4.26 (t, J=6.8, 1H), 3.99-3.92 (m, 2H).

EXAMPLE 11 6-Acetylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound213, Structure 7 of Scheme II, Where R¹=H, R²=Acetyl)

This compound was prepared from Compound 200 and acetic anhydride by thefollowing General Procedure VII (Acylation of amine):

To a solution of an amine such as Compound 200 (Structure 3 of SchemeII) in methylene chloride (0.1-0.5 M) was added an acid chloride oranhydride (1.5 equiv) and triethylamine (1.5 equiv) and the resultingmixture was stirred at room temperature for 1 h till the reaction wentcompletion. The mixture was quenched with water and extracted withEtOAc. Removal of solvent and chromatography afforded the amide in goodyield. Compound 213 was isolated as a yellow solid: ¹H NMR (500 MHz,acetone-d₆) 11.0 (bs, 1H), 9.4 (bs, 1H), 8.23 (s, 1H), 7.91 (dd, J=8.8,2.4, 1H), 7.46 (d, J=8.8, 1H), 6.93 (s, 1H), 2.11 (s, 3H).

EXAMPLE 12 6-Trifluoroacetylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 214, Structure 7 of Scheme II, Where R¹=H, R²=Trifluoroacetyl)

This compound was prepared in a similar fashion as that described inExample 11, General Procedure VII but using trifluoroacetic anhydride inplace of acetic anhydride. Compound 214 was isolated as a yellow solid:¹H NMR (500 MHz, acetone-d₆) 11.2 (bs, 1H), 10.5 (bs, 1H), 8.25 (t,J=2.0, 1H), 8.04 (dd, J=8.8, 2.4, 1H), 7.58 (d, J=8.8, 1H), 7.00 (s,1H).

EXAMPLE 13 6-Benzoylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound215, Structure 7-of Scheme II, Where R¹=H, R²=Benzoyl)

This compound was prepared in a similar fashion as that described inExample 11, General Procedure VII but using benzoyl chloride in place ofacetic anhydride. Compound 215 was isolated as a yellow solid: ¹H NMR(500 MHz, DMSO-d₆) 12.3 (bs, 1H), 10.5 (bs, 1H), 8.38 (s, 1H), 8.06 (dd,J=8.8, 0.9, 1H), 7.98 (d, J=6.8, 2H), 7.62-7.59 (m, 1H), 7.56-7.53 (m,2H), 7.43 (d, J=8.8, 1H), 7.00 (s, 1H).

EXAMPLE 14 6-Dimethylacetylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 216, Structure 7 of Scheme II, Where R¹=H, R²=Dimethylacetyl)

This compound was prepared in a similar fashion as that described inExample 11, General Procedure VII but using isobutyric anhydride inplace of acetic anhydride. Compound 216 was isolated as a yellow solid:¹H NMR (500 MHz, acetone-d₆) 11.1 (bs, 1H), 9.3 (bs, 1H), 8.30 (t,J=1.9, 1H), 7.95 (dd, J=8.8, 2.4, 1H), 7.47 (d, J=8.8, 1H), 6.94 (s,1H), 2.68-2.62 (m, 1) 1.19 (d, J=6.8, 6H).

EXAMPLE 15 6-Dimethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound217, Structure 7 of Scheme II, Where R¹═R²=Methyl)

This compound was prepared from Compound 200 and formaldehyde by thefollowing General Procedure VIII (Dialkylation of amine):

To a solution of Compound 200 (Structure 3 of Scheme II) (35 mg, 0.15mmol) in methanol (20 mL) was added an aldehyde (2-5 equiv) followed byNaCNBH₃ (2-5 equiv). The mixture was stirred at room temperature for 4 hand water (20 mL) was added. The water layer was extracted with EtOAc(2×20 mL) and the combined organic layers were washed with brine anddried over MgSO₄. Concentration and purification by flash chromatography(silica gel, hex/EtOAc 3:1) afforded the mono-alkylated product as ayellow solid (70-95%). Repeating the same procedure in the presence ofthe second aldehyde or ketone afforded the dialkylated product (50-90%).In case that both alkyl groups were same, the double alkylation wascarried out in one step, in which a catalytic amount of acetic acid wasneeded to accelerate the reaction. The acetic acid was also needed whena ketone was used as an alkylating agent.

Compound 217 was isolated as a bright yellow solid: ¹H NMR (500 MHz,acetone-d₆) 10.9 (bs, 1H), 7.42 (d, J=9.3, 1H), 7.28 (dd, J9.3, 2.9,1H), 6.94 (s, 1H), 6.89 (s, 1H), 2.99 (s, 6H).

EXAMPLE 16 6-Diethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound218, Structure 7 of Scheme II, Where R¹═R²=Ethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetaldehyde in place ofparaformaldehyde. Compound 218 was isolated as a yellow solid: ¹H NMR(500 MHz, CDCl₃) 10.3 (bs, 1H), 7.18 (d, J=9.3, 1H), 7.07 (dd, J=9.3,2.4, 1H), 7.03(s, 1H), 6.95 (s, 1H), 3.39 (q, J=6.8, 4H), 1.18 (t,J=6.8, 6H).

EXAMPLE 17 6-Dipropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound219, Structure 7 of Scheme II, Where R¹═R²=Propyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using propionaldehyde in place ofparaformaldehyde. Compound 219 was isolated as a yellow solid: ¹H NMR(500 MHz, CDCl₃) 11.0 (bs, 1H); 7.22 (d, J=9.3, 1H), 7.03 (dd, J=9.3,2.4, 1H), 7.03 (s, 1H), 6.90 (s, 1H), 3.28 (t, J=7.3, 4H), 1.66-1.58 (m,4H), 0.95 (t, J=7.3, 6H).

EXAMPLE 18 6-Dibutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound220, Structure 7 of Scheme II, Where R¹═R²=Butyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using butyraldehyde in place ofparaformaldehyde. Compound 220 was isolated as a yellow solid: ¹H NMR(500 MHz, CDCl₃) 12.2 (bs, 1H), 7.32 (d, J=8.8, 1H), 7.06 (dd, J=8.8,2.4, 1H), 7.04 (s, 1H), 6.90 (s, 1H), 3.31 (t, J=6.8, 4H), 1.60-1.50 (m,4H), 1.41-1.33 (m, 4H), 0.97 (t, J=7.3, 6H).

EXAMPLE 19 6-Diisobutylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 221, Structure 7 of Scheme II, Where R¹═R²=Isobutyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using isobutyraldehyde in placeof paraformaldehyde. Compound 221 was isolated as a yellow solid: ¹H NMR(500 MHz, CDCl₃) 11.7 (bs, 1H), 7.27 (d, J=9.3, 1H), 7.06 (dd, J=9.3,2.9, 1H), 7.04 (s, 1H), 6.90 (s, 1H), 3.18 (d, J=6.8, 3H), 2.09-2.02 (m,2H), 0.92 (d, J=6.3, 12H).

EXAMPLE 206-(bis-Cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 222, Structure 7 of Scheme II, Where R¹═R²=Cyclopropylmethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using cyclopropanecarboxaldehydein place of paraformaldehyde. Compound 222 was isolated as a yellowsolid: ¹H NMR (500 MHz, CDCl₃) 11.5 (bs, 1H), 7.29 (d, J=9.3, 1H), 7.22(dd, J=9.3, 2.4, 1H), 7.12 (s, 1H), 7.05 (s, 1H), 2.31 (d, J=5.8, 4H),1.07-1.01 (m, 2H), 0.57-0.53 (m, 4H), 0.26-0.23 (m, 4H).

EXAMPLE 216-(bis-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 223, Structure 7 of Scheme II, WhereR¹═R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroaldehydesequentially in place of paraformaldehyde alone. Compound 223 wasisolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 10.99 (s, 1H), 7.44(d, J=8.9, 1H), 7.32 (s, 1H), 7.29 (d, J=8.9, 1H), 7.11 (s, 1H), 4.07(q, J=8.4, 4H).

EXAMPLE 226-(bis-2,2,3,3,3-Pentafluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 224, Structure 7 of Scheme II, WhereR¹═R²=Pentafluoroethylmethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using2,2,3,3,3-pentafluoropropyraldehyde in place of paraformaldehyde.Compound 224 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)11.1 (bs, 1H), 7.35 (s, 1H), 7.34 (d, J=8.8, 1H), 7.28 (dd, J=8.8, 2.4,1H), 7.10 (s, 1H), 4.14 (t, J=16.9, 4H).

EXAMPLE 236-(bis-2-Chloro-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 225, Structure 7 of Scheme II, WhereR¹═R²=Chlorodifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using chlorodifluoroacetic acid inplace of difluoroacetic acid. Compound 225 was isolated as a yellowsolid: ¹H NMR (400 MHz, acetone-d₆) 11.12 (bs, 1H), 7.66 (dd, J=2.6,9.1, 1H),7.50(d, J=9.1, 1H), 7.46 (s, 1H), 6.95 (s, 1H), 4.55 (t,J=12.1, 4H).

EXAMPLE 24 6-(bis-2-Bromoethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 226, Structure 7 of Scheme II, Where R¹═R²=2-Bromoethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using bromoacetic acid in place ofdifluoroacetic acid. Compound 226 was isolated as a yellow solid: ¹H NMR(CDCl₃) 11.06(bs, 1H), 7.41 (d, J=9.0, 1H), 7.12 (d, J=9.0, 1H), 7.09(s, 1H), 6.98 (s, 1H), 3.85 (t, J=7.2, 4H), 3.50 (t, J=7.2, 4H).

EXAMPLE 256-(N-2,2,2-Trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 227, Structure 7 of Scheme II, Where R¹=H,R²=2,2,2-Trichloroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 200 (Structure 3 of SchemeII) and trichloroacetic acid. Compound 227 was isolated as a yellowsolid: ¹H NMR (CDCl₃) 10.53 (bs, 1H), 7.40 (d, J=9.6, 1H), 7.15 (d,J=9.6, 1H), 7.13 (s, 1H), 7.09 (s, 1H), 4.62 (t, J=7.2, 1H), 4.19 (d,J=7.2, 2H).

EXAMPLE 266-(bis-N-2,2,2-Trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 228, Structure 7 of Scheme II, WhereR¹═R²=2,2,2-Trichloroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 200 (Structure 3 of SchemeII) and trichloroacetic acid. Compound 228 was isolated as a yellowsolid: ¹H NMR (CDCl₃) 10.82 (bs, 1H), 7.65 (s, 1H); 7.57 (d, J=8.8, 1H),7.45 (d, J=8.8, 1H), 7.10 (s, 1H), 4.70 (s, 4H).

EXAMPLE 276-(N-2,2,2-Chlorodifluoroethyl-N-2,2,2-Trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 229, Structure 7 of Scheme II, WhereR¹=2,2,2-Chlorodifluoroethyl, R²=2,2,2-Trichloroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 200 (Structure 3 of SchemeII) and trichloroacetic acid and chlorodifluoroacetic acid. Compound 229was isolated as a yellow solid: ¹H NMR (CDCl₃) 10.86(bs, 1H), 7.34 (d,J=9.0, 1H), 7.21 (dd, J=9.1, 2.6, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 5.97(tt, J=55, 3.8, 1H), 3.83 (td, J=13.9, 3.9, 4H).

EXAMPLE 286-(bis-N-2,2-Difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 230, Structure 7 of Scheme II, Where R¹═R²=2,2-Dilfuoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 200 (Structure 3 of SchemeII) and difluoroacetic acid. Compound 230 was isolated as a yellowsolid: ¹H NMR (CDCl₃) 11.47 (bs, 1H), 7.34 (d, J=9.0, 1H), 7.21 (dd,J=9.1, 2.6, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 5.97 (tt, J=55, 3.8, 1H),3.83 (td, J=13.9, 3.9, 4H).

EXAMPLE 296-(N-2,2-Dichloroethyl-N-2,2,2-trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 231, Structure 7 of Scheme II, Where R¹=2,2,2-Trichloroethyl,R²=2,2-Dichloroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 200 (Structure 3 of SchemeII) and dichloroacetic acid and trichloroacetic acid. Compound 231 wasisolated as a yellow solid: ¹H NMR (CDCl₃) 11.01 (bs, 1H), 7.44 (s, 2H),7.42 (s, 1H), 7.41(s, 1H), 7.12 (s, 1H), 5.74 (t, J=6.3, 1H), 4.58 (s,2H) 4.33 (d, J=6.3, 2H).

EXAMPLE 306-(bis-N-2,2-Dichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 232, Structure 7 of Scheme II, Where R¹═R²=2,2-Dichloroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 200 (Structure 3 of SchemeII) and dichloroacetic acid. Compound 232 was isolated as a yellowsolid: ¹H NMR (400 MHz, acetone-d₆) 11.2 (bs, 1H), 7.51 (s, 2H), 7.19(s, 1H), 6.94 (s, 1H), 6.25 (t, J=6.3, 2H), 4.29 (d, J=6.3, 4H).

EXAMPLE 316-(N-2,2-Dichloroethyl-N-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 233, Structure 7 of Scheme II, Where R¹=2,2-Dichloroethyl,R²=2,2-Difluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 200 (Structure 3 of SchemeII) and dichloroacetic acid and difluoroacetic acid. Compound 233 wasisolated as a yellow solid: ¹H NMR (CDCl₃): 10.60 (bs, 1H), 7.47 (d,J=9.1, 1H), 7.2 (dd, J=9.1, 2.6, 1H), 7.11 (s, 2H), 5.95 (tt, J=55, 3.8,1H), 5.87 (t, J=6.2, 1H), 4.1 (d, J=6.2, 2H), 3.94, (td, J=13.9, 3.9,2H).

EXAMPLE 326-(N-2,2-Dichloroethyl-N-2,2,2-chlorodifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 234, Structure 7 of Scheme II, Where R¹=2,2-Dichloroethyl,R²=2,2,2-Chlorodifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 200 (Structure 3 of SchemeII) and dichloroacetic acid and chlorodifluoroacetic acid. Compound 234was isolated as a yellow solid: ¹H NMR (CDCl₃) 11.21 (bs, 1H), 7.43 (d,J=9.0, 1H), 7.24 (d, J=9.0, 1H), 7.21(s, 1H), 7.11 (s, 1H), 5.84 (t,J=6.2, 1H), 4.3 (t, J=11.5, 2H), 4.15 (d, J=6.2, 2H).

EXAMPLE 336-(N-Isopropyl-N-methyl)amino-4-trifluoromethyl-2(1)-quinolinone(Compound 235, Structure 7 of Scheme II, Where R¹=Methyl, R²=Isopropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using paraformaldehyde andacetone sequentially in place of paraformaldehyde alone. Compound 235was isolated as a yellow solid: ¹H NMR (500 MHz, acetone-d₆) 10.9 (bs,1H), 7.41 (d, J=9.3, 1H), 7.36 (dd, J=9.3, 2.9, 1H), 7.00 (bs, 1H) 6.88(s, 1H), 4.16-4.11 (m, 1H), 2.78 (s, 3H), 1.19 (d, J=6.8, 6H).

EXAMPLE 346-(N-Methyl-N-cyclopentyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 236, Structure 7 of Scheme II, Where R¹=Cyclopentyl,R²=Methyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using paraformaldehyde andcyclopentanone sequentially in place of paraformaldehyde alone. Compound236 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 11.4 (bs,1H), 7.28 (d, J=8.8, 1H), 7.25 (dd, J=8.8, 2.4, 1H), 7.10 (s, 1H), 7.06,1H), 4.14-4.06 (m, 1H), 2.84 (s, 3H), 1.94-1.87 (m, 2H), 1.78-1.73 (m,2H), 1.67-1.59 (m, 4H).

EXAMPLE 356-(N-Methyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 237, Structure 7 of Scheme II, Where R¹=Methyl, R²=Isobutyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using paraformaldehyde andisobutyraldehyde sequentially in place of paraformaldehyde alone.Compound 237 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)11.0 (bs, 1H), 7.25 (d, J=9.3, 1H), 7.08 (dd, J=9.3, 2.9, 1H), 7.04 (s,1H), 6.93 (s, 1H), 3.14 (d, J=7.3, 2H), 3.01 (s, 3H), 2.08-2.03 (m, 1H),0.94 (d, J=6.8, 6H).

EXAMPLE 36 6-(N-Ethyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 238, Structure 7 of Scheme II, Where R¹=Propyl, R²=Ethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using propyraldehyde andacetaldehyde sequentially in place of paraformaldehyde alone. Compound238 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 10.7 (bs,1H), 7.21 (d, J=9.3, 1H), 7.06, (dd, J=9.3, 2.4, 1H), 7.03 (s, 1H), 6.93(s, 1H), 3.41 (q, J=7.3, 2H), 3.25 (t, J=7.3, 2H), 1.66-1.61 (m, 2H),1.18 (t, J=7.3, 3H), 0.97 (t, J 7.3, 3H).

EXAMPLE 376-(N-Ethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 239, Structure 7 of Scheme II, Where R¹=Isopropyl, R²=Ethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetaldehyde and acetonesequentially in place of paraformaldehyde alone. Compound 239 wasisolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 11.6 (bs, 1H), 7.29(d, J=8.8, 1H), 7.17, (dd, J=8.8, 2.9, 1H), 7.05 (s, 1H), 7.03 (s, 1H),4.04-3.99 (m, 1H), 3.28 (q, J=6.8, 2H), 1.22 (d, J=6.8, 6H), 1.18 (t,J=6.8, 3H).

EXAMPLE 386-N-Ethyl-N-1-metylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 240, Structure 7 of Scheme II, Where R¹=Ethyl,R²=1-Methylpropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetaldehyde and 2-butanonesequentially in place of paraformaldehyde alone. Compound 240 wasisolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 11.5(bs, 1H),7.27(d, J=9.3, 1H), 7.16 (dd, J=9.3, 2.4, 1H), 7.04 (s, 1H), 7.02 (s,1H), 3.76-3.69 (m, 1H), 3.33-3.24 (m, 2H), 1.71-1.62 (m, 1H), 1.54-1.49(m, 1H), 1.19 (d, J=6.8, 3H), 1.17 (t, J=6.8, 3H), 0.93 (t, J=7.3, 3H).

EXAMPLE 396-(N-Ethyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 241, Structure 7 of Scheme II, Where R¹=Ethyl, R²=Isobutyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetaldehyde andisobutyraldehyde sequentially in place of paraformaldehyde alone.Compound 241 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)11.6 (bs, 1H), 7.28 (d, J=9.3, 1H), 7.07 (dd, J=9.3, 2.4, 1H), 7.04 (s,1H), 6.92 (s, 1H), 3.43 (q, J=6.8, 2H), 3.08 (d, J=7.3, 2H), 2.03-2.01(m, 1H), 1.15 (t, J=6.8, 3H), 0.95 (d, J=6.8, 6H).

EXAMPLE 406-(N-Ethyl-N-2,2-dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 242, Structure 7 of Scheme II, Where R¹=Ethyl,R²=2,2-Dimethylpropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetaldehyde andtrimethylacetaldehyde sequentially in place of paraformaldehyde alone.Compound 242 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)11.2 (bs, 1H), 7.23 (d, J 8.8, 1H), 7.07 (dd, J=8.8, 2.9, 1H), 7.05 (s,1H), 7.03 (s, 1H), 3.47 (q, J=6.8, 2H), 3.12 (s, 2H), 1.11 (t, J 6.8,3H), 0.99 (s, 9H).

EXAMPLE 416-(N-Ethyl-N-cyclopentyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 243, Structure 7 of Scheme II, Where R¹=Cyclopentyl, R²=Ethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetaldehyde andcyclopentanone sequentially in place of paraformaldehyde alone. Compound243 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 11.6 (bs,1H), 7.29 (d, J=9.3, 1H), 7.22, (dd, J=9.3, 2.4, 1H), 7.12 (s, 1H), 7.06(s, 1H), 3.98-3.93 (m, 1H), 3.32 (q, J=7.3, 2H), 1.98-1.95 (m, 2H),1.77-1.73 (m, 2H), 1.66-1.62 (m, 2H), 1.59-1.53 (m, 2H), 1.14 (t, J=7.3,3H).

EXAMPLE 426-(N-Ethyl-N-1-acetylethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 244, Structure 7 of Scheme II, Where R¹=Ethyl,R²=1-Acetylethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetaldehyde and2,3-butanedione sequentially in place of paraformaldehyde alone.Compound 244 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)11.6 (bs, 1H), 7.31 (d, J=8.8, 1H), 7.10 (dd, J=8.8, 2.4, 1H), 7.07 (s,1H), 7.01 (s, 1H), 4.21 (q, J=6.8, 1H), 3.42-3.30 (m, 2H), 2.18 (s, 3H),1.39 (d, J=6.8, 3H), 1.22 (t, J=7.3, 3H).

EXAMPLE 43(±)-6-(N-Ethyl-N-1-methyl-2-hydroxypropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 245, Structure 7 of Scheme II, Where R¹=Ethyl,R²=1-Methyl-2-hydroxypropyl)

This compound was prepared by sodium borohydride reduction of Compound244 (Structure 7 of Scheme II, where R¹=ethyl, R²=1-acetylethyl) inmethanol. Compound 245 was isolated as a yellow solid: ¹H NMR (500 MHz,acetone-d₆) 10.9 (bs, 1H), 7.40-7.39 (m, 2H), 7.12, (s, 1H), 6.88 (s,1H), 3.93-3.82 (m, 1H), 3.65 (d, J=2.9, 1H), 3.61-3.56 (m, 1H),3.42-3.37 (m, 2H), 1.21-1.13 (m, 9H).

EXAMPLE 446-(N-Ethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 246, Structure 7 of Scheme II, Where R¹=Ethyl,R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetaldehyde andtrifluoroacetaldehyde sequentially in place of paraformaldehyde alone.Compound 246 was isolated as a yellow solid: ¹H NMR (400 MHz,acetone-d₆) 11.02 (s, 1H), 7.46 (d, J=9.1, 1H), 7.38 (dd, J=9.1, 2.7,1H), 7.10 (s, 1H), 6.92 (s, 1H), 4.18 (q, J=9.3, 2H), 3.61 (q, J=7.0,2H), 1.22 (t, J=7.0, 3H).

EXAMPLE 456-(-Ethyl-N-3-furylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 247, Structure 7 of Scheme II, Where R¹=Ethyl,R²=3-Furylmethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetaldehyde and3-furaldehyde sequentially in place of paraformaldehyde alone. Compound247 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 11.3 (bs,1H), 7.37 (t, J=1.0, 1H), 7.30 (s, 1H), 7.25 (d, J=9.3, 1H), 7.13 (dd,J=9.3, 2.4, 1H), 7.04 (s, 2H), 6.30 (s, 1H), 4.36 (s, 2H), 3.46 (q,J=7.3, 2H), 1.20 (t, J=7.3, 3H).

EXAMPLE 46(±)-6-(N-Ethyl-N-2,2-dimethoxyisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 248, Structure 7 of Scheme II, Where R¹=Ethyl,R²=2,2-Dimethoxyisopropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetaldehyde andα,α-dimethoxyacetone sequentially in place of paraformaldehyde alone.Compound 248 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)11.4 (bs, 1H), 7.27 (d, J=9.3, 1H), 7.20, (dd, J=9.3, 2.4, 1H), 7.08 (s,1H), 7.05 (s, 1H), 4.23 (d, J=5.4, 1H), 3.93 (dq, J=6.8, 5.4, 1H), 3.43(s, 3H), 3.42-3.33 (m, 2H), 3.35 (s, 3H), 1.26 (d J=6.8, 3H), 1.17 (t,J=7.3, 3H).

EXAMPLE 476-(N-Isopropyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 249, Structure 7 of Scheme II, Where R¹=Propyl, R²=Isopropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using propyraldehyde and acetonesequentially in place of paraformaldehyde alone. Compound 249 wasisolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 12.1 (bs, 1H), 7.33(d, J=9.3, 1H), 7.15 (dd, J=9.3, 2.4, 1H), 7.05 (s, 1H), 7.00 (s, 1H),4.04-3.99 (m, 1H), 3.11 (t, J=6.8, 1H), 1.60-1.54 (m, 2H), 1.20 (d,J=6.3, 6H), 0.95 (t, J=7.3, 3H)

EXAMPLE 486-(N-2-Hydroxyethyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 250, Structure 7 of Scheme II, Where R¹=2-Hydroxyethyl,R²=Propyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using propyraldehyde and glyoxalsequentially in place of paraformaldehyde alone. Compound 250 wasisolated as a yellow solid: ¹H NMR (500 MHz, acetone-d₆) 10.8 (bs, 1H),7.38 (d, J=9.3, 1H), 7.25 (dd, J=9.3, 2.9, 1H), 6.93 (s, 1H), 6.86 (s,1H), 3.85 (t, J=5.8, 1H), 3.75 (dt, J=7.8, 5.8, 2H), 3.53 (t, J=6.3,2H), 3.39 (t, J=7.8, 2H), 1.67-1.61 (m, 2H), 0.95 (t, J=7.3, 3H).

EXAMPLE 49(±)-6-(N-Propyl-N-1-methylbutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 251, Structure 7 of Scheme II, Where R¹=Propyl,R²=1-Methylbutyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using propyraldehyde and3-methyl-2-butanone sequentially in place of paraformaldehyde alone.Compound 251 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃),11.7 (bs, 1H), 7.29 (d, J=8.8, 1H), 7.15 (dd, J=8.8, 2.5, 1H), 7.04 (s,1H), 6.99 (s, 1H), 3.84-3.80 (m, 1H), 3.12-3.09 (m, 2H), 1.65-1.31 (m,6H), 1.17 (d, J=6.3, 3H), 0.94 (t J=7.3, 3H), 0.91 (t, J=7.3, 3H).

EXAMPLE 50(±)-6-(N-Propyl-N-1,2-dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 252, Structure 7 of Scheme II, Where R¹=Propyl,R²=1,2-Dimethylpropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using propyraldehyde and3-methyl-2-butanone sequentially in place of paraformaldehyde alone.Compound 252 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)10.8 (bs, 1H), 7.21 (d, J=9.3, 1H), 7.16, (dd, J=9.3, 2.4, 1H), 7.03 (s,1H), 6.98 (s, 1H), 3.42-3.39 (m, 1H), 3.12 (t, J=6.8, 2H), 1.92-1.86 (m,1H), 1.61-1.55 (m, 2H), 1.19 (d, J=6.3, 3H), 0.99 (d, J=6.3, 3H), 0.97(t, J=7.3, 3H), 0.91 (d, J=6.3, 3H).

EXAMPLE 516-(N-Propyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 253, Structure 7 of Scheme II, Where R¹=Propyl, R²=Isopropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using propyraldehyde andisobutyraldehyde sequentially in place of paraformaldehyde alone.Compound 253 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)11.5 (bs, 1H), 7.26 (d, J=8.8, 1H 7.05, (dd, J=8.8, 2.4, 1H), 7.03 (s,1H), 6.90 (s, 1H), 3.31 (t, J=7.3, 2H), 3.11 (d, J=7.3, 2H), 2.05-2.00(m, 1H), 1.64-1.58 (m, 2H), 0.94 (d, J=6.8, 6H), 0.93 (t, J=7.3, 3H).

EXAMPLE 526-(N-Propyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 254, Structure 7 of Scheme II, Where R¹=Propyl,R²=Cyclopropylmethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using propyraldehyde andcyclopropanecarboxaldehyde sequentially in place of paraformaldehydealone. Compound 254 was isolated as a yellow solid: ¹H NMR (500 MHz,CDCl₃) 9.9 (bs, 1H), 7.15 (d, J=8.8, 1H), 7.12 (dd, J=8.8, 2.4, 1H),7.02 (s, 1H), 7.00 (s, 1H), 3.35 (t, J=6.8, 2H), 3.24 (d, J=6.3, 2H),1.66-1.61 (m, 2H), 1.04-1.01 (m, 1H), 0.95 (t, J=7.3, 3H), 0.57-0.55 (m,2H), 0.26-0.24 (m,2H).

EXAMPLE 53(±)-6-(N-Propyl-N-1-methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 255, Structure 7 of Scheme II, Where R¹=Propyl, R²=sec-Butyl)

This compound was prepared in a similar,fashion as that described inExample 15, General Procedure VIII but using propyraldehyde and2-butanone sequentially in place of paraformaldehyde alone. Compound 255was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 11.2 (bs, 1H),7.25 (dd, J=9.3, 2.4, 1H), 7.15 (dd, J=9.3, 2.4, 1H), 7.03 (s, 1H), 7.00(s, 1H), 3.70 (q, J=6.8, 1H), 3.12-3.09 (m, 2H), 1.58-1.47 (m, 2H), 1.18(d, J=6.3, 3H), 0.93-0.91 (m, 6H).

EXAMPLE 546-(N-2-Hydroxyethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H-quinolinone(Compound 256, Structure 7 of Scheme II, Where R¹=2-Hydroxyethyl,R²=Isopropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetone and glyoxalsequentially in place of paraformaldehyde alone. Compound 256 wasisolated as a yellow solid: ¹H NMR (500 MHz, acetone-d₆) 10.9 (bs, 1H),7.41 (d, J=8.8, 1H), 7.37 (dd, J=8.8, 2.9, 1H), 7.10 (s, 1H), 6.88 (s,1H), 4.09-4.03 (m, 1H), 3.83 (t, J=5.6, 1H), 3.68 (dt, J=6.8, 5.6, 2H),3.38 (t, J=6.8, 2H), 1.23 (d, J=6.8, 6H).

EXAMPLE 556-(N-Isopropyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 257, Structure 7 of Scheme II, Where R¹=Isopropyl,R²=Cyclopropylmethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using acetone andcyclopropanecarboxaldehyde sequentially in place of paraformaldehydealone. Compound 257 was isolated as a yellow solid: ¹H NMR (500 MHz,CDCl₃) 11.0 (bs, 1H), 7.19 (s, 2H), 7.04 (s, 2H), 4.03-3.98 (m, 1H),3.08 (d, J=5.4, 2H), 1.21 (d, J=6.4, 6H), 0.98-0.93 (m, 1H),0.58-0.55(m, 2H), 0.26-0.23 (m, 2H).

EXAMPLE 566-(N-Methyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 258, Structure 7 of Scheme II, Where R¹=Methyl,R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using paraformaldehyde andtrifluoroacetaldehyde sequentially. Compound 258 was isolated as ayellow solid: ¹H NMR (500 MHz, CDCl₃) 11.3 (bs, 1H), 7.31 (d, J=9.3,1H), 7.18 (dd, J=9.3, 2.9, 1H), 7.11 (s, 1H), 7.08 (s, 1H), 3.91 (q,J_(H-F)=8.8, 2H), 3.13 (s, 3H).

EXAMPLE 576-(N-2,2,2-Trifluoroethyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 259, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=Isobutyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde andisobutyraldehyde sequentially in place of paraformaldehyde alone.Compound 259 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)11.31 (s, 1H), 7.29 (d, J=9.3, 1H), 7.23 (d, J=9.3, 1H), 7.19 (s, 1H),7.06 (s, 1H), 3.94 (q, J=8.9, 2H), 3.25 (d, J=7.3, 2H), 2.09-2.03 (m,1H), 0.94 (d, J=6.3, 6H).

EXAMPLE 586-(N-2,2,2-Trifluoroethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 260, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=Isopropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde andisopropyraldehyde sequentially in place of paraformaldehyde alone.Compound 260 was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃)11.10 (s, 1H), 7.45 (d, J=9.1, 1H), 7.33 (dd, J=9.1, 2.6, 1H), 7.30 (s,1H), 7.11 (s, 1H), 4.07-3.95 (m, 1H), 3.83 (q, J=8.8, 2H), 1.24 (d,J=6.6, 6H).

EXAMPLE 596-N-2,2,2-Trifluoroethyl-N-Cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 261, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=Cyclopropylmethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde andcyclopropanecarboxaldehyde sequentially in place of paraformaldehydealone. Compound 261 was isolated as a yellow solid: ¹H NMR (400 MHz,CDCl₃) 10.83 (s, 1H), 7.42 (d, J=9.0, 1H), 7.27 (dd, J=9.0, 2.7, 1H),7.22 (d, J=2.7, 1H), 7.09 (s, 1H), 4.03 (q, J=8.8, 2H), 3.34 (d, J=6.3,2H), 1.09-1.00 (m, 1H), 0.64-0.59 (m, 2H), 0.31-0.27 (m, 2H).

EXAMPLE 60(±)-6-(N-2,2,2-Trifluoroethyl-N-1-methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 262, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=sec-Butyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde and2-butanone sequentially in place of paraformaldehyde alone. Compound 262was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 10.87 (s, 1H),7.30-7.23 (m, 3H), 7.05 (s, 1H), 3.81 (q, J=8.6, 2H), 3.63-3.58 (m, 1H),1.21 (d, J=6.7, 3H), 1.02-0.86 (m, 5H).

EXAMPLE 61(±)-6-(N-2,2,2-Trifluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 263, Structure 7of Scheme II Where R¹=2,2,2-Trifluoroethyl,R²=2-chloroisopropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde andchloroacetone sequentially. Compound 263 was isolated as a yellow solid:¹H NMR (400 MHz, acetone-d₆) 10.99 (s, 1H), 7.43 (s, 2H), 7.13 (s, 1H),6.90 (s, 1H), 4.35 (q, J=7.8, 2H), 4.22-4.17 (m, 1H), 3.61 (dd, J=15.3,3.6, 1H), 3.42 (dd, J=15.3, 8.3, 1H), 1.20 (d, J=6.2, 3H).

EXAMPLE 62(+)-6-(N-2,2,2-Trifluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 264, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=2-chloroisopropyl) and(−)-6-(N-2,2,2-Trifluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 265, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=2-Chloroisopropyl)

Compounds 264 and 265 were prepared by chiral HPLC separation ofCompound 263.

EXAMPLE 636-(N-2,2,2-Trifluoroethyl-N-3-furfuryl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 266, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=3-Furanylmethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde and3-furaldehyde sequentially. Compound 266 was isolated as a yellow solid:¹H NMR (400 MHz, acetone-d₆) 10.98 (s, 1H), 7.77 (s, 1H), 7.43 (s, 3H),7.19 (s, 1H, 6.89 (s, 1H), 6.42 (s, 1H), 4.62 (s, 2H), 6.27 (q, J=9.1,2H).

EXAMPLE 646-(N-2,2,2-Trifluoroethyl-N-3-thiophenemethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 267, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=3-Thiophenemethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde and3-thiophenecarboxaldehyde sequentially. Compound 267 was isolated as ayellow solid: ¹H NMR (400 MHz, acetone-d₆) 10.99 (s, 1H), 7.31-7.29 (m,3H), 7.13 (s, 1H), 7.02 (s, 1H), 6.92 (d, J=4.6, 1H), 6.76 (s, 1H), 4.66(s, 2H), 4.21 (q, J=9.2, 2H).

EXAMPLE 656-(N-2,2,2-Trifluoroethyl-N-3,3-dimethylbutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 268, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=3,3-Dimethylbutyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde and3,3-dimethylbutyraldehyde sequentially. Compound 268 was isolated as ayellow solid: ¹H NMR (400 MHz, acetone-d₆) 10.99 (s, 1H), 7.33 (d,J=9.2, 1H), 7.21 (dd, J=9.1, 2.6, 1H), 6.97 (s, 1H), 6.79 (s, 1H), 4.06(q, J=9.2, 2H), 3.45 (m, 2H), 1.45 (m, 2H), 0.88 (s, 9H).

EXAMPLE 666-(N-2,2,2-Trifluoroethyl-N-2-thiophenemethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 269, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=2-Thiophenemethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde and2-thiophenecarboxaldehyde sequentially. Compound 269 was isolated as ayellow solid: ¹H NMR (400 MHz, acetone-d₆) 10.92 (s, 1H), 7.45-7.42 (m,3H), 7.33 (d, J=5.4, 1H), 7.24 (s, 1H), 7.08 (s, 1H), 6.96 (t, J=4.4,1H), 6.88 (s, 1H), 4.96 (s, 2H), 4.31 (q, J=9.0, 2H).

EXAMPLE 676-(N-2,2,2-Trifluoroethyl-N-2-furfuryl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 270, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=2-Furanylmethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde and2-furaldehyde sequentially. Compound 270 was isolated as a yellow solid.¹H NMR (400 MHz, acetone-d₆) 10.92 (s, 1H), 7.50 (s, 1H), 7.47-7.42 (m,2H), 7.25 (s, 1H), 6.89 (s, 1H), 6.37-6.34 (m, 2H), 4.72 (s, 2H), 4.29(q, J=9.2, 2H).

EXAMPLE 686-(N-Butyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 271, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=Butyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde andbutyraldehyde sequentially. Compound 271 was isolated as a yellow solid.¹H NMR (400 MHz, acetone-d₆) 11.04 (s, 1H), 7.45 (d, J=9.1, 1H), 7;37(dd, J=9.1, 2.5, 1H), 7.10 (s, 1H), 6.91 (s, 1H), 4.19 (q, J=9.3, 2H),3.52 (t, J=7.7, 2H), 1.9-1.61 (m, 2H), 1.46-1.37 (m, 2H), 0.96 (t,J=7.4, 3H).

EXAMPLE 69 6-(bis-N,N-Benzyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 272, Structure 7 of Scheme II, Where R¹═R²=Benzyl;

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using benzaldehyde. Compound 272was isolated as a yellow solid. ¹H NMR (400 MHz, acetone-d₆) 11.60 (s,1H), 7.41-7.25 (m, 12H), 6.98 (s, 1H), 6.83 (s, 1H), 4.79 (s, 4H).

EXAMPLE 706-(N-2,2,2-Trifluoroethyl-N-cyclobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 273, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=Cyclobutyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde andcyclobutanone sequentially in place of paraformaldehyde alone. Compound293 was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 10.85 (s,1H), 7.30-7.25 (m, 2H), 7.16 (s, 1H), 7.06 (m, 1H), 4.18-4.08 (m, 1H),3.86 (q, J=8.9, 2H), 2.40-2.34 (m, 2H), 1.97-1.92 (m, 2H), 1.79-1.77 (m,2H).

EXAMPLE 716-(N-2,2,2-Trifluoroethyl-N-2,2-dichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 274, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=2,2-Dichloroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using trifluoroacetic acid anddichloroacetic acid sequentially in place of difluoroacetic acid.Compound 274 was isolated as a yellow solid: ¹H NMR (400 MHz,acetone-d₆) 11.26 (s, 1H), 7.58 (dd, J=9.2, 2.7, 1H), 7.50 (d, J=9.1,1H), 7.32 (s, 1H), 6.97 (s, 1H), 6.26 (t, J=6.4, 1H), 4.45 (q, J=9.0,2H), 4.23 (d, J=6.4, 2H).

EXAMPLE 726-(N-2,2,2-Trifluoroethyl-N-2-chloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 275, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=2-Chloroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using trifluoroacetic acid andchloroacetic acid sequentially in place of difluoroacetic acid. Compound275 was isolated as a yellow solid: ¹H NMR (400 MHz, acetone-d₆) 11.10(s, 1H), 7.48 (d, J=2.5, 2H), 7.17 (s, 1H), 6.93 (s, 1H), 4.34 (q,J=9.2, 2H), 3.92 (dd, J=13.9, 7.1, 2H), 3.80 (dd, J=13.9, 7.1, 2H).

EXAMPLE 736-(N-Benzyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 276, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=Benzyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde andbenzaldehyde sequentially in place of paraformaldehyde alone. Compound276 was isolated as a yellow solid: ¹H NMR (400 MHz, acetone-d₆) 11.62(s, 1H), 7.39 (d, J=2.3, 2H), 7.38-7.31 (m, 4H), 7.27-7.22 (m, 1H), 7.09(s, 1H), 6.86 (s, 1H), 4.81 (s, 2H), 4.41 (q, J=9.2, 2H).

EXAMPLE 746-(N-4-Fluorobenzyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 277, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=Benzyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde and4-fluorobenzaldehyde sequentially in place of paraformaldehyde alone.Compound 277 was isolated as a yellow solid: ¹H NMR (400 MHz,acetone-d₆) 11.05 (s, 1H), 7.40 (s, 1H), 7.39-7.34 (m, 3H), 7.10-7.06(m, 3H), 6.86 (s, 1H), 4.80 (s, 2H), 4.41 (q, J=9.2, 2H).

EXAMPLE 756-(N-Propyl-N-2,2,2-trifluoroethyl)amino4-trifluoromethyl-2(1H)-quinolinone(Compound 278, Structure 7 of Scheme II, Where R¹=Propyl,R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde andpropyraldehyde sequentially in place of paraformaldehyde alone. Compound278 was isolated as a yellow solid: ¹H NMR (400 MHz, acetone-d₆) 11.03(s, 1H), 7.45 (d, J=9.1, 1H), 7.38 (dd, J=9.1, 2.3, 1H), 7.09 (s, 1H),6.91 (s, 1H), 4.24-4.17 (m, 2H), 3.48 (t, J=7.6, 2H).

EXAMPLE 766-(N-2,2,3,3,3-Pentafluoropropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 279, Structure 7 of Scheme II, WhereR¹=2,2,3,3,3-Pentafluoropropyl, R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde andpentafluoropropyraldehyde sequentially in place of paraformaldehydealone. Compound 279 was isolated as a yellow solid: ¹H NMR (500 MHz,CDCl₃) 11.8 (bs, 1H), 7.39 (d, J=8.8, 1H), 7.33 (s, 1H), 7.29 (dd,J=8.8, 2.9, 1H), 7.10 (s, 1H), 4.13 (t, J_(H-F)=15.1, 2H), 4.08 (q,J_(H-F)=8.3, 2H).

EXAMPLE 77 6-Diallylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound280, Structure 7 of Scheme II, Where R¹═R³=Allyl)

This compound was prepared from Compound 200 and allyl bromide by thefollowing General Procedure IX (Allylation of amine):

To a solution of Compound 200 (Structure 3 of Scheme II) in methanol(0.05-0.2 M) was added K₂CO₃ powder (5-10 equiv) and an allyl bromide(3-10 equiv). The reaction mixture was stirred at room temperature for 3hrs and extracted with EtOAc. The organic layer was washed with H₂O,dried (Na₂SO₄), and concentrated in vacuo. Purification bychromatography afforded a white solid in excellent yield (80-95%).

Compound 280 was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃)11.01 (s, 1H), 7.27 (d, J=2.6, 1H), 7.20 (d, J=9.1, 1H), 7.07 (dd,J=9.1, 2.6, 1H), 7.02 (s, 1H), 5.90-5.81 (m, 2H), 3.20 (dd, J=15.6, 3.9,4H), 397 (d, J=3.9, 4H).

EXAMPLE 786-(N-Isobutyl-N-allyl)amino-4-trifluoromethyl-2(1H-quinolinone (Compound281, Structure 7 of Scheme II, Where R¹=Isobutyl, R²=Allyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII to install isobutyl fromisobutyraldehyde and sequentially in a similar fashion as that describedin Example 77, General Procedure IX to install allyl group from allylbromide. Compound 281 was isolated as a yellow solid: ¹H NMR (500MHz,CDCl₃) 11.2 (bs, 1H), 7.23 (d, J=9.3, 1H), 7.06 (dd, J=9.3, 2.4, 1H),7.03 (s, 1H), 6.97 (s, 1H), 5.85-5.77 (m, 1H), 5.19-5.12 (m, 2H),4.00-3.99 (m, 2H), 3.15 (d, J=7.3, 2H), 2.09-2.03 (m, 1H), 0.97 (d,J=6.8, 6H).

EXAMPLE 796-(N-Isopropyl-N-allyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 282, Structure 7 of Scheme II, Where R¹=Isopropyl, R²=Allyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII to install isopropyl fromisopropyraldehyde and sequentially in a similar fashion as thatdescribed in Example 77, General Procedure IX to install allyl groupfrom allyl bromide. Compound 282 was isolated as a yellow solid: ¹H NMR(500 MHz, CDCl₃) 10.8 (bs, 1H), 7.21 (d, J=9.3, 1H), 7.13 (dd, J=9.3,2.4, 1H), 7.06 (s, 1H), 7.02 (s, 1H), 5.89-5.82 (m, 1H), 5.26 (dd,J=17.1, 1.5, 1H), 5.18 (dd, J=10.3, 1.5, 1H), 4.12-4.07 (m, 1H),3.84-3.83 (m, 2H), 1.22 (d, J=6.4, 6H).

EXAMPLE 806-(N-Allyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 283, Structure 7 of Scheme II, Where R¹=Allyl,R²=2,2,2-Trifluoroethyl)

6-Allylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 284,Structure 7 of Scheme II, where R¹=allyl, R²=H):

To a solution of Compound 200 (Structure 3 of Scheme II) (340 mg, 1.49mmol) in MeOH (20 mL) was added K₂CO₃ (1.0 g) followed by allylbromide(0.30 mL, 3.5 mmol). After stirring at room temperature for 6 h, waterwas added and the mixture was extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine, and dried over MgSO₄,concentrated in vacuo and purified by column chromatography (Silica gel,hex:EtOAc, 3:1 to 1:1 gradient) to give 184 mg of Compound 284.

6-(N-Allyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 283, Structure 7 of Scheme II, where R¹=allyl,R²=2,2,2-trifluoroethyl):

To a solution of Compound 284 (261 mg, 0.97 mmol) in TFA (8 mL) wasadded trifluoroacetaldehyde hydrate (0.5 mL, 5 mmol) and the mixture wasstirred at room temperature for 6 h. NaCNBH₃ (60 mg, 1 mmol) was addedand the mixture was stirred for 16 h. Then additional NaCNBH₃ (60 mg, 1mmol) was added and the mixture was stirred for 2 h. The reaction wasquenched with water (20 mL) and was extracted with EtOAc (2×40 mL). Thecombined organic layer was dried over MgSO₄, concentrated in vacuo andpurified by column chromatography (Silica gel, hex:EtOAc 5:2) to giveCompound 283 (201 mg, 0.57 mmol) as a yellow solid: ¹H NMR (500 MHz,CDCl₃) 2.0 (bs, 1H), 7.35 (d, J=9.8, 1H), 7.19-7.16 (m, 2H), 7.08 (s,1H), 5.87-5.80 (m, 1H), 5.27 (dd, J=10.7, 1.5, 1H), 5.19 (dd, J=17.6,1.5, 1H), 4.10 (d, J=4.9, 2H),3.92 (q, J_(H-F)=8.8, 2H).

EXAMPLE 816-(N-Allyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 285, Structure 7 of Scheme II, Where R¹=Allyl,R²=Cyclopropylmethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII to install cyclopropylmethyl groupfrom cyclopropanecarboxaldehyde and sequentially in a similar fashion asthat described in Example 77, General Procedure IX to install allylgroup from allyl bromide. Compound 285 was isolated as a yellow solid:¹H NMR (400 MHz, CDCl₃) 10.7 (bs, 1H), 7.38 (d, J=9.1, 1H), 7.15 (dd,J=9.1, 2.5, 1H), 7.06 (s, 1H), 7.05 (s, 1H), 5.90-5.80 (m, 1H), 5.20 (d,J=5.4, 1H), 5.17 (s, 1H), 4.04 (d, J=4.7, 2H), 3.27 (d, J=6.2, 2H),1.08-1.03 (m, 1H), 0.59-0.55 (m, 2H), 0.27-0.23 (m, 2H).

EXAMPLE 826-(N-Allyl-N-2,2,2-trifluoroacetyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 286, Structure 7 of Scheme II, Where R¹=Allyl,R²=2,2,2-Trifluoroacetyl)

This compound was prepared in a similar fashion as that described inExample 11, General Procedure VII but using Compound 284 (Structure 7 ofScheme II, where R¹=H, R²=allyl) and trifluoroacetic anhydride in placeof Compound 200 and acetic anhydride. Compound 286 was isolated as awhite solid: ¹H NMR (500 MHz, CDCl₃) 12.9 (bs, 1H), 7.69 (s, 1H), 7.57(d, J=8.8, 1H), 7.48 (dd, J=8.8, 2.4, 1H), 7.17 (s, 1H), 5.90-5.87 (m,1H), 5.26 (d, J=9.8, 1H), 5.14 (d, J=17.1, 1H), 4.36 (s, 2H).

EXAMPLE 836-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroacetyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 287, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=Trifluoroacetyl)

This compound was prepared in a similar fashion as that described inExample 11, General Procedure VII but using Compound 209 (Structure 7 ofScheme II, where R¹=H, R²=2,2,2-Trifluoroethyl) and trifluoroaceticanhydride in place of Compound 200 and acetic anhydride. Compound 287was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 11.57 (s, 1H),7.78 (s, 1H) 7.53-7.32 (m, 2H), 7.17 (s, 1H), 4.45-4.39 (m, 2H).

EXAMPLE 84 6-(N-Allyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 288, Structure 7 of Scheme II, Where R¹=Allyl, R²=Propyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII to install propyl group frompropionaldehyde and sequentially in a similar fashion as that describedin Example 77, General Procedure IX to install allyl group from allylbromide. Compound 288 was isolated as a yellow solid: ¹H NMR (500 MHz,CDCl₃) 10.9 (bs, 1H), 7.21 (d, J=9.3, 1H), 7.05 (dd, J=9.3, 2.9, 1H),7.03 (s, 1H), 6.96 (s, 1H), 5.87-5.80 (m, 1H), 5.19-5.16 (m, 2H), 3.96(d, J=4.9, 2H), 3.31 (t, J=7.3, 2H), 1.67-1.61 (m, 2H), 0.96 (t, J=7.3,3H).

EXAMPLE 85(±)-6-(N-2-Hydroxyisopropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 289, Structure 7 of Scheme II, Where R¹=2-Hydroxysopropyl,R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde andacetol sequentially in place of paraformaldehyde alone. Compound 289 wasisolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 11.6 (bs, 1H), 7.44(s, 1H), 7.41 (dd, J=8.8, 2.4, 1H), 7.35 (d, J=8.8, 1H), 7.09 (s, 1H),3.96-3.88 (m, 1H), 3.85-3.78 (m, 2H), 3.67-3.61 (m, 2H), 2.06 (d, J=1.4,1H), 1.14 (d, J=6.8, 3H).

EXAMPLE 86(±)-6-(N-Isobutyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 290, Structure 7 of Scheme II, Where R¹=Isobutyl,R²=2,2,2-Trifluoroisopropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetone and2-butanone sequentially in place of paraformaldehyde alone. Compound 290was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 12.3 (bs, 1H),7.38 (d, J=8.8, 1H), 7.30 (dd, J=8.8, 2.4, 1H), 7.28 (s, 1H), 7.09 (s,1H), 4.12-4.06 (m, 1H), 3.05 (d, J=7.3, 2H), 1.83-1.78 (m, 1) 1.41 (d,J=6.8, 3H), 0.89-0.87 (m, 6H).

EXAMPLE 876-(N-2,2-Difluoroethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 291, Structure 7 of Scheme II, Where R¹=2,2-Difluoroethyl,R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 211 (Structure 7 ofScheme II, where R¹=H, R²=2,2-difluoroethyl) and trifluoroacetic acid inplace of Compound 200 and difluoroacetic acid. Compound 291 was isolatedas a yellow solid: ¹H NMR (400 MHz, acetone-d₆) 11.55 (s, 1H), 7.54 (dd,J=9.1, 2.4, 1H), 7.49 (d, J=9.1, 1H), 7.29 (s, 1H), 6.96 (s, 1H), 6.21(tt, J=55.5, 3.9, 1H), 4.37 (m, 2H), 4.02 (td, J 14.2, 3.9, 2H).

EXAMPLE 886-(N-2,2-Dimethylpropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 292, Structure 7 of Scheme II, Where R¹=2,2-Dimethylpropyl,R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 211 (Structure 7 ofScheme II, where R¹=H, R²=2,2-difluoroethyl) and trimethylacetic acid inplace of Compound 200 and difluoroacetic acid. Compound 292 was isolatedas a yellow solid: ¹H NMR (400 MHz, acetone-d₆) 12.2 (bs, 1H), 7.36 (d,J=9.8, 1H), 7.33-7.31 (m, 2H), 7.09 (s, 1H) 4.03 (q, J_(H-F)=8.8, 2H),3.36 (s, 2H), 0.94 (s, 9H).

EXAMPLE 896-(N-2,2-Difluoro-2-chloroethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 293, Structure 7 of Scheme II, WhereR¹=2,2-Difluoro-2-chloroethyl, R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 209 (Structure 7 ofScheme II, where R¹=H, R²=2,2,2-Trifluoroethyl) and chlorodifluoroaceticacid in place of Compound 200 and difluoroacetic acid. Compound 293 wasisolated as a yellow solid: ¹H NMR (400 MHz, acetone-d₆) 11.18 (s, 1H),7.64 (dd, J=9.1, 2.4, 1H), 7.52 (d, J=9.1, 1H), 7.43 (s, 1H), 6.99 (s,1H), 4.52 (t, J=12.1, 2H), 4.43 (m, 2H).

EXAMPLE 906-(N-2,2-Difluoro-2-chloroethyl-N-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 294 Structure 7 of Scheme II, Where R¹=2,2-Difluoroethyl,R²=2,2-Difluoro-2-chloroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 211 (Structure 7 ofScheme II, where R¹=H, R²=2,2-difluoroethyl) and chlorodifluoroaceticacid in place of Compound 200 and difluoroacetic acid. Compound 294 wasisolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 7.44 (d, J=9.2, 1H),7.27 (m, 2H), 7.11 (s, 1H), 5.97 (tt, J=3.9, 55.8 Hz), 4.20 (t, J=11.7,2H), 3.90 (td, J_(d)=3.8, J_(t)=13.6, 2H).

EXAMPLE 916-(N-2,2,2-Trifluoroethyl-N-methylsufonyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 295, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=Methylsulfonyl)

To pyridine (0.3 mL) was added Compound 209 (Structure 7 of Scheme II,where R¹=H, R²=2,2,2-Trifluoroethyl) (10.0 mg, 0.03 mmol) followed bymethanesulfonyl chloride (6.8 mg, 0.06 mmol) and the reaction mixtureheated at 60° C. for 18 h. The cooled reaction mixture was diluted withEtOAc and with water. The organic layers were dried over MgSO₄,concentrated in vacuo, and chromatographed (MeOH:CH₂Cl₂, 1:19) toproduce 2.2 mg (19%) Compound 295 as a brown solid: R_(f)0.80(MeOH:CH₂Cl₂, 1:19); ¹H NMR (400 MHz, CDCl₃) 7.90 (d, J=9.1, 1H), 7.46(s, 1H), 7.26-7.28 (m, 1H), 7.13 (s, 1H), 3.93 (quin, J=7.3, 2H), 3.60(s, 3H).

EXAMPLE 921-Methyl-6-(N-propyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 296, Structure 9 of Scheme II, Where R¹=Propyl, R²=Isobutyl,R³=Methyl)

This compound was prepared from Compound 243 and iodomethane by thefollowing General Procedure X (Methylation of amide):

To a solution of a 2-quinolinone, such as Compound 253 (Structure 7 ofScheme II, where R¹=propyl, R²=isobutyl) in THF (0.05-0.2 M) was addedsodium hydride (60% in mineral oil, 1.2-2.0 equivalents) and iodomethane(2-5 equivalents), the resulting mixture was stirred at room temperaturefor 1 h until the alkylation went completion by TLC. The mixture wasquenched with water, extracted with EtOAc, and concentrated.Chromatography of the crude mixture afforded the N-alkylated product inexcellent yield (80-95%).

Compound 296 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)7.30 (d, J=9.3, 1H), 7.07 (dd, J=9.3, 2.9, 1H), 7.07 (s, 1H), 6.97 (s,1H), 3.71 (s, 3H), 3.33 (t, J=7.3, 2H), 3.13 (d, J=7.3, 2H), 2.07-2.01(m, 1H), 1.64-1.59 (m, 2H), 0.96-0.93 (m, 9H).

EXAMPLE 931-Methyl-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 297, Structure 9 of Scheme II, WhereR¹═R²=2,2,2-Trifluoroethyl, R³=Methyl)

This compound was prepared in a similar fashion as that described inExample 92, General Procedure X but using Compound 223 (Structure 7 ofScheme II, where R¹═R²=2,2,2-Trifluoroethyl) in place of Compound 253.Compound 297 was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃)7.39 (d, J=9.4, 1H), 7.36 (s, 1H), 7.30 (d, J=9.4, 1H), 7.12 (s, 1H),4.11-4.05 (m, 2H), 3.73 (s, 3H).

EXAMPLE 941-Ethyl-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 298, Structure 9 of Scheme II, WhereR¹═R²=2,2,2-Trifluoroethyl, R³=Ethyl)

This compound was prepared in a similar fashion as that described inExample 92, General Procedure X from Compound 223 (Structure 7 of SchemeII, where R¹═R²=2,2,2-Trifluoroethyl) and iodoethane. Compound 298 wasisolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 7.41 (d, J=9.3, 1H),7.36 (s, 1H), 7.30 (dd, J=9.3, 2.9, 1H), 7.12 (s, 1H), 4.36 (q, J=7.3,2H), 4.08 (q, J_(H-F)=8.8, 4H), 1.37 (t, J=7.3, 3H).

EXAMPLE 956-(N-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-thioquinolinone(Compound 299, Structure 8 of Scheme II, Where R¹=H,R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 209 by the following GeneralProcedure XI (Thioamide formation):

An amide such as Compound 209 (Structure 7 of Scheme II, where R¹=H,R²=2,2,2-Trifluoroethyl) in toluene (0.2-1.0 M) was treated withLawsson's reagent (1.2 equiv). The reaction mixture was then stirred atroom temperature overnight, diluted with EtOAc, washed with sat. NaHCO₃,water, brine, dried (MgSO₄), filtered and concentrated under reducedpressure to yield crude product. Purification by column chromatography(15-50% EtOAc/hexane) afforded the thioamide in good yield as a yellowsolid.

Compound 299 was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃)10.39 (s, 1H), 7.66 (d, J=9.1, 1H), 7.50 (s, 1H), 7.36 (dd, J=9.1, 2.4,1H), 7.10 (s, 1H), 6.20 (s, 1H), 4.09 (m, 2H).

EXAMPLE 966-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-thioquinolinone(Compound 300, Structure 8 of Scheme II, WhereR¹═R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 223 (Structure 7 of Scheme II,where R¹═R²=2,2,2-Trifluoroethyl) by General Procedure XI described inExample 95. Compound 300 was isolated as yellow solid. ¹H NMR (CDCl₃,500 MHz) 12.0 (bs, 1H), 7.74 (s, 1H), 7.48 (d, J=9.3, 1H), 7.27-7.33 (m,2H), 4.12 (q, J=7.8, 4H).

EXAMPLE 97(±)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 301, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=2,2,2-Trifluoroisopropyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using trifluoroacetaldehyde andtrifluoroacetone sequentially in place of paraformaldehyde alone.Compound 301 was isolated as a yellow solid: ¹H NMR (400 MHz,acetone-d₆) 11.10 (s, 1H), 7.68 (d, J=2.4, 1H), 7.66 (d, J=2.4, 1H),7.55(dd, J=1.7, 21.1, 1H), 6.96 (s, 1H), 4.36 (s, 1H), 4.23 (dq, J=2,2, 8.8,2H), 1.47 (d, J=7.0, 3H).

EXAMPLE 98(+)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 302, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=2,2,2-Trifluoroisopropyl) and(−)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 303, Structure 7 of Scheme II, Where R¹=2,2,2-Trifluoroethyl,R²=2,2,2-Trifluoroisopropyl)

Compounds 302 and 303 were prepared by chiral HPLC separation ofCompound 301.

EXAMPLE 99 6-Mercapto-4-trifluoromethyl-2(1H)-quinolinone (Compound 305,Structure 13 of Scheme II)

6-Methoxythiocarbonylmercapto-4-trifluoromethyl-2(1H)-quinolinone(Compound 304, Structure 12 of Scheme II)

To a mixture of Compound 200 (Structure 3 of Scheme II) in H₂SO₄ wasadded aqueous NaNO₂ at 0° C. and the resulting mixture was stirred for 1h to give 6-diazo-4-trifluoromethyl-2(1H)-quinolinone (Structure 11 ofScheme II). To a solution of potassium O-ethylxanthate in water at 50°C. was added the above crude mixture and the reaction was stirred for 2hand cooled down to rt. The mixture was extracted with EtOAc, washed withbrine and concentrated. Chromatography afforded Compound 304 as a whitesolid. ¹H NMR (400 MHz, CDCl₃) 11.29 (s, 1H), 7.99 (s, 1H), 7.72 (dd,J=8.6, 1.7, 1H), 7.50 (d, J=8.6, 1H), 7.14 (s, 1H), 7.03 (s, 1H), 4.63(q, J=7.2, 2H), 1.35 (t, J=7.2, 3H).

6-Mercapto-4-trifluoromethyl-2(1H)-quinolinone (Compound 305, Structure13 of Scheme II):

To a solution of Compound 304 in THF was added LiAlH₄ in THF at 0° C.and the reaction mixture was warmed to rt till the starting material wasconsumed by TLC. The reaction was quenched with water, neutralized withHCl (3N aqueous), extracted and washed with brine. Removal of solventand chromatography afforded Compound 305 as white solids. ¹H NMR (400MHz, CDCl₃) 11.02 (s, 1H), 7.73 (s, 1H), 7.54 (d, J=8.7, 1H), 7.48 (d,J=8.7, 1H), 7.08 (s, 1H), 3.62 (s, 1H).

EXAMPLE 1006-(1,1-Dimethyl-2-propynyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 306, Structure 10 of Scheme II)

In a r.b. flask, a solution of compound 200 (Structure 3 of Scheme II)in THF was treated with Cu(I)Cl (10 mol %) and2-acetoxy-2-methyl-3-butyne (1.5 equiv). The reaction mixture was heatedto reflux for 18 h. After cooling to rt, the reaction mixture wasfiltered through a pad of celite and the celite cake was rinsed withEtOAc. The filtrate was washed with saturated aqueous NH₄Cl solution,H₂O, and brine. Dried (MgSO₄), filtered, and concentrated in vacuo. Theresidue was purified by flash column chromatography (SiO₂, 5% EtOAc inhexane as eluent) to afford compound 306 as a yellow solid. ¹H NMR (500MHz, CDCl₃) 12.9 (bs, 1H), 7.49 (s, 1H), 7.38 (d, J=8.8, 1H), 7.20 (dd,J=8.8, 2.4, 1H), 7.08 (s, 1H), 3.81 (bs, 1H), 2.42 (s, 1H), 1.63 (s,6H).

EXAMPLE 101 6-tert-Butylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 307, Structure 7 of Scheme III, Where R¹=H, R²=tert-Butyl)

6-Bromo-4-trifluoromethyl-2(1H)-quinolinone (Compound 308, Structure 16of Scheme III):

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 4-bromoaniline in place ofaniline. Compound 308 was isolated in 40-60% yield as a white solid: ¹HNMR (400 MHz, acetone-d₆) 10.60 (s, 1H), 7.74 (dd, J=8.8, 1.9, 1H), 7.48(d, J=8.8, 1H), 6.99 (s, 1H).

6-Bromo-4-trifluoromethyl-2-isopropyloxyquinoline (Compound 309,Structure 17 of Scheme III):

This compound was prepared by the following General Procedure XII:

To a solution of Compound 308 (0.40 g, 1.4 mmol) in DMF (7 mL) was addedCsF (0.88 g, 5.8 mmol) and 2-iodopropane (0.66 g, 2.7 mmol) and thereaction mixture was stirred at room temperature overnight till thestarting material was consumed. The resulting brown suspension wasdiluted with EtOAc (50 mL), washed with water (3×50 mL) and brine andconcentrated. Chromatography afforded the 2-isopropyloxyquinoline in50-90% yield.

Compound 309 was isolated as white crystalline needles (0.24 g, 51%): ¹HNMR (400 MHz, CDCl₃) 8.10 (d, J=0.9, 1H), 7.74 (s, 2H), 7.19 (s, 1H),5.57-5.51 (m, 1H), 1.41 (d, J=6.2, 6H).

6-tert-Butylamino-2-isopropyloxy-4-trifluoromethylquinolines (Compound310, Structure 18 of Scheme III, where R¹=H, R²=tert-butyl):

This compound was prepared by the following General Procedure XIII(Palladium mediated coupling of aryl bromide and alkylamine):

To a schlenk tube containing absolution of a bicyclic aryl bromide, suchas Compound 309 in toluene (0.05-0.2 M) was added Cs₂CO₃ (2-3 equiv),Pd₂(dba)₃ (1-3 mol %), and (R)-BINAP (2.0 mg, 0.003 mmol, 1.5-4.5 mol %)followed by a primary or secondary amine (3-5 equiv). The resultingyellow reaction mixture was heated to 100° C. for 4-48 h, cooled to roomtemperature, diluted with Et₂O, filtered, and concentrated in vacuo.Chromatography (CH₂Cl₂:hexane or EtOAc:hexane mixtures) of the crudemixture afforded compounds of Structures 18 or 19.

Compound 310 was isolated as green oils.

6-tert-Butylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 307,Structure 7 of Scheme III, where R¹H, R²=tert-butyl):

This compound was prepared by the following General Procedure XIV(Hydrolysis of 2-alkyloxyquinoline):

To a 50 mL r.b. flask containing a solution of2-(isopropylether)-6-alkylamino-4-trifluoromethyl quinoline such asCompound 310 (0.1 mmol) in AcOH (0.5 mL) was added conc. HCl (0.2 mL)and the reaction mixture stirred at rt for 30 min and 100° C. for 30min. The cooled reaction mixture was diluted with CH₂Cl₂ (25 mL) andneutralized by the dropwise addition of sat. NaHCO₃ (approx. 25 mL). Theorganic layers were washed with sat. NaHCO₃ (50 mL) and H₂O (50 mL) andthe aqueous layers were back extracted with EtOAc (25 mL). The combinedorganic layers were dried over MgSO₄, concentrated in vacuo, andpurified by flash chromatography (MeOH:CH₂Cl₂, 1:4 or 1:9) to affordcompounds of Structures 7 or 14 in Scheme III (25-95%).

Compound 307 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)12.2-12.4 (bs, 1H), 7.30 (d, J=8.8, 1H), 7.15 (bs, 1H), 7.03-7.06 (m,2H), 1.37 (s, 9H).

EXAMPLE 102 6-(1-Piperidinyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 311, Structure 20 of Scheme III, Where R³⁻⁸=H, X=Methylene)

This compound was prepared in a similar fashion as described in Example101, General Procedures XIII and XIV from Compound 309 and piperidine asa yellow solid: R_(f)0.51 (MeOH:CH₂Cl₂, 1:9); ¹H NMR (500 MHz,d₆-acetone) 10.92 (bs, 1H), 7.42-7.45 (m, 2H), 7.15 (d, J=2.0, 1H), 6.89(s, 1H), 3.17(t, J=5.4, 4H), 1.73 (quin, J=5.9, 4H), 1.56-1.62 (m, 2H).

EXAMPLE 103 6-(1-Pyrrolidinyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 312, Structure 20 of Scheme III Where R³⁻⁸=H, X=a Bond)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but using pyrrolidine inplace of piperidine. Compound 312 was isolated as a yellow solid:R_(f)0.55 (MeOH:CH₂Cl₂, 1:9); ¹H NMR (500 MHz, d₆-acetone) 7.41 (d,J=9.3, 2H), 7.07 (dd, J=2.9, 9.3, 1H), 6.87 (s, 1H), 3.31-3.34 (m, 4H),2.02-2.04 (m, 4H).

EXAMPLE 104 6-(1-Morpholino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 313, Structure 20 of Scheme III, Where R³⁻⁸=H, X=Oxygen)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but using morpholine inplace of piperidine. Compound 313 was isolated as a yellow solid:R_(f)0.35 (MeOH:CH₂Cl₂ 1:4); ¹H NMR (500 MHz, d₆-acetone) 7.46-7.47 (m,2H), 7.15-7.16 (m, 1H), 6.91 (s, 1H), 3.82-3.84 (m, 4H), 3.16-3.18 (m,4H).

EXAMPLE 105(±)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 314, Structure 20 of Scheme III, Where R⁴⁻⁸=H, R³=Methyl,X=Methylene)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but using2-methylpiperidine in place of piperidine. Compound 314 was isolated asa yellow solid: R_(f)0.75 (MeOH:CH₂Cl₂, 1:4); ¹H NMR (500 MHz, CDCl₃)12.57 (bs, 1H), 7.34-7.41(m, 2H), 7.23-7.26 (m, 1H), 7.08 (s, 1H),3.85-3.86 (m, 1H), 3.15-3.17 (m, 1H), 3.03 (t, J=8.8, 1H), 1.61-1.91(m,6H), 0.99 (d, J=6.8, 3H).

EXAMPLE 106(+)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 315, Structure 20 of Scheme III, Where R⁴⁻⁸=H, R³=Methyl,X=Methylene) and(−)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 316, Structure 20 of Scheme III, Where R⁴⁻⁸=H, R³=Methyl,X=Methylene)

Compounds 315 and 316 were prepared by chiral HPLC separation ofCompound 314. Compound 315: [α]_(D)=+23 and Compound 316: [α]_(D)=−30.

EXAMPLE 107 6-(N-Phenylamino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 317, Structure 7 of Scheme III, Where R¹=Phenyl, R²=H)

6-(N-phenylamino)-4-trifluoromethyl-2-isopropyloxyquinoline (Compound318, Structure 18 of Scheme III, where R¹=phenyl, R²=H):

This compound was prepared in a similar fashion as that described inExample 101, General Procedure XIII from aniline.

6-(N-phenylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 317,Structure 7 of Scheme III, where R¹=phenyl, R²=H):

This compound was prepared in a similar fashion as that described inExample 101, General Procedure XIV from Compound 318. Compound 317 wasisolated as a yellow solid. ¹H NMR (400 MHz, CDCl₃) 10.83 (s, 1H),7.47-7.38 (m, 3H), 7.32-7.26 (m, 2H), 7.09-7.04 (m, 3H), 6.98 (t, J=7.3,1H), 5.86 (s, 1H).

EXAMPLE 1086-(N-Phenyl-N-ethylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound319, Structure 7 of Scheme III, Where R¹=Phenyl, R²=Ethyl)

6-(N-phenyl-N-ethylamino)-4-trifluoromethyl-2-isopropyloxyquinoline(Compound 320, Structure 18 of Scheme III, where R¹=phenyl, R²=ethyl):

A mixture of Compound 318 (Structure 18 of Scheme III, where R¹=phenyl,R²=H), iodoethane and NaH in THF was stirred at rt overnight till thestarting material was consumed. The reaction was quenched with water,extracted with EtOAc and concentrated. Chromatography afforded Compound320 as yellow oil.

6-(N-phenyl-N-ethylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound319, Structure 7 of Scheme III, where R¹=phenyl, R²=ethyl):

This compound was prepared in a similar fashion as that described inExample 101, General Procedure XIV from Compound 320. Compound 319 wasisolated as a yellow solid. ¹H NMR (400 MHz, CDCl₃) 11.27 (s, 1H),7.37-7.27 (m, 6H), 7.01-6.99 (m, 3H), 3.82 (q, J=7.0, 2H), 1.25 (t,J=7.0, 3H).

EXAMPLE 1096-Phenyl-N-2,2,2-trifluoroethylamino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 321, Structure 7 of Scheme III, Where R¹=Phenyl,R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV from Compound 317 and2,2,2-trifluoroacetaldehyde. Compound 321 was isolated as a yellowsolid. ¹H NMR (400 MHz, acetone-d₆) 11.60 (s, 1H), 7.54 (d, J=8.7, 1H),7.49-7.44 (m, 2H), 7.34-7.30 (m, 2H), 7.05-7.00 (m, 3H), 6.95 (s, 1H),4.61(q, J=9.1, 2H).

EXAMPLE 110(±)-6-(3-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 322, Structure 20 of Scheme III, Where R³⁻⁴=R⁶⁻⁸=H, R=Methyl,X=Methylene)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but using3-methylpiperidine in place of piperidine. Compound 322 was isolated asa yellow solid: R_(f)0.81(EtOAc); ¹H NMR (500 MHz, CDCl₃) 10.6-10.8 (bs,1H), 7.33 (dd, J=2.9, 9.3, 1H), 7.15-7.24 (m, 2H), 7.05 (s, 1H),3.51-3.58 (m, 2H), 2.69 (dt, J=2.9, 11.7, 1H), 2.38 (t, J=10.7, 1H),1.71-1.85 (m, 3H), 1.68-1.71(m, 1), 1.05-1.11(m, 1), 0.99 (d, J=6.3,3H).

EXAMPLE 1116-(4-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound323, Structure 20 of Scheme III, Where R³⁻⁸=H, X=CHCH₃)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but using4-methylpiperidine in place of piperidine. Compound 323 was isolated asa yellow solid: R_(f)0.51(MeOH:CH₂Cl₂, 1:4); ¹H NMR (500MHz d₆-acetone)7.42-7.45 (m, 2H), 7.15 (s, 1H), 6.89 (s, 1H), 3.66 (d, J=12.2, 2H),2.65-2.74 (m, 2H), 1.79 (d, J=11.7, 2H), 1.50-1.60 (m, 1H), 1.32-1.38(m, 2H), 0.99 (d, J=6.3, 3H).

EXAMPLE 1126-(cis-3,5-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 324, Structure 20 of Scheme III, Where R³⁻⁴=R⁷⁻⁸H,R⁵⁻⁶=Methyl, X=Methylene)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but usingcis-3,5-dimethylpiperidine in place of piperidine. Compound 324 wasisolated as a yellow solid: R_(f)0.71 (MeOH:CH₂Cl₂, 1:4); ¹H NMR (500MHz, CDCl₃) 10.2-10.4 (bs, 1H), 7.32 (dd, J=2.4, 9.3, 1H), 7.14-7.22 (m,2H), 7.05 (s, 1H), 3.55 (d, J=11.2, 2H), 2,26 (t, J=11.2, 2H), 1.83-1.85(m, 3H), 0.97 (d, J=6.8, 3H), 0.71-0.74 (m, 1H).

EXAMPLE 1136-(2,6-cis-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 325, Structure 20 of Scheme III, Where R⁴⁻⁷=H, R³═R⁸=Methyl,X=Methylene) and(±)-6-(2,6-trans-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 326, Structure 20 of Scheme III, Where R⁴⁻⁷=H, R³=R⁸=Methyl,X=Methylene)

These compounds were prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but using2,6-dimethylpiperidine in place of piperidine. Compounds 325 and 326were isolated as a 1:1mixture as a yellow solid: Compound 325: ¹H NMR(500 MHz, CDCl₃) 11.80-12.00 (bs, 1H), 7.34 (s, 2H), 7.21 (s, 1H), 7.08(s, 1H), 3.56-3.64 (m, 2H), 2.75 (dt, J=2.4, 12,2, 1H), 2.38 (t, J=10.7,1H), 1.68-1.85 (m, 2H), 1.35-1.43 (m, 1H), 1.21-1.28 (m, 1H), 0.99 (d,J=6.4, 6H); Compound 326: ¹H NMR (500 MHz, CDCl₃) 11.80-12.00 (bs, 1H),7.34 (s, 2H), 7.21 (s, 1H), 7.08 (s, 1H), 3.49-3.54 (m, 2H), 2.69 (dt,J=2.9, 11.7, 1H), 1.68-1.85 (m, 3H), 1.21-1.28 (m, 1H), 1.06-1.11 (m,1H), 1.01(d, J=6.3, 6H);

EXAMPLE 114(±)-6-(2-Methyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 327, Structure 20 of Scheme III, Where R⁴⁻⁸=H, R³=Methyl, X=aBond)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but using2-methylpyrrolidine in place of piperidine. Compound 327 was isolated asa yellow solid: R_(f)0.68 (MeOH:CH₂Cl₂, 1:4); ¹H NMR (500 MHz, CDCl₃)11.6-11.8 (bs, 1H, 7.31(d, J=9.3, 1H), 7.06 (bs, 1H), 6.99 (dd, J=2.4,9.3, 1H), 6.83 (m, 1H), 3.91-3.94 (m, 1H), 3.48 (dt, J=2.9, 9.8, 1H),3.22 (q, J=7.3, 1H), 2.10-2.16 (m, 2H), 2.02-2.10 (m, 1H), 1.76-1.77 (m,1H), 1.21 (d, J=6.3, 3H).

EXAMPLE 1156-(2,5-cis-Dimethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 328, Structure 20 of Scheme III, Where R⁴⁻⁷=H, R³═R⁸=Methyl,X=a Bond)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but using2,5-dimethylpyrrolidine in place of piperidine. Compound 328 wasisolated as a yellow solid: R_(f)0.60 (MeOH:CH₂Cl₂, 1:4); ¹H NMR (500MHz, CDCl₃) 11.4-11.8 (bs, 1H), 7.28-7.30 (m, 1H), 7.05 (bs, 1H), 7.02(dd, J=2.4, 9.3, 1H), 6.86-6.90 (m, 1H), 3.79-3.82 (m, 2H), 2.08-2.14(m, 2H), 1.75-1.80 (m, 2H), 1.31(d, J=6.8, 6H).

EXAMPLE 116(±)-6-(2,5-trans-Dimethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 329, Structure 20 of Scheme III, Where R⁴⁻⁷=H, R³═R⁸=Methyl,X=a Bond)

Compound 329 was isolated as a miner isomer of Compound 328 as describedin Example 115 as a yellow solid: R_(f)0.60 (MeOH:CH₂Cl₂, 1:4); ¹H NMR(400 MHz, CDCl₃) 11.2-11.4 (bs, 1H), 7.32 (d, J=8.9, 1H), 6.90-7.01 (m,2H), 6.78-6.82 (m, 1H), 3.88-4.06 (m, 2H), 2,26-2,28 (m, 2H), 1.67-1.69(m, 2H), 1.12 (d, J=6.2, 6H).

EXAMPLE 117 6-(1-Azepano)-4-trifluoromethyl-2(1H)-quinolinone (Compound330, Structure 20 of Scheme III, Where R³⁻⁸=H, X=Ethylene)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but using azepane in placeof piperidine. Compound 330 was isolated as a yellow solid: R_(f)0.52(MeOH:CH₂Cl₂, 1:9); ¹H NMR (500 MHz, CDCl₃) 9.80 (bs, 1H), 7.14 (s, 1H),7.07 (dd, J=2.4, 9.3, 1H), 7.02 (bs, 1H), 6.93-6.95 (m, 1H), 3.51 (t,J=5.9, 4H), 1.57-1.82 (m, 4H), 1.55-1.60 (m; 4H).

EXAMPLE 118(±)-6-(2-Hydroxyethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 331, Structure 20 of Scheme III, Where R⁴⁻⁸=H,R³=Hydroxymethyl, X=Methylene)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but using2-(tert-butyldimethylsilyloxymethyl)piperidine in place of piperidine.The silyl protection group was removed under the HCl hydrolysiscondition. Compound 331 was isolated as a yellow solid: R_(f)0.28(MeOH:CH₂Cl₂, 1:4); ¹H NMR (500 MHz, CDCl₃) 11.7-11.9 (bs, 1H), 7.40(J=2.4, 1H), 7.32-7.34 (m, 2H), 7.07 (bs, 1H), 3.78-3.82 (m, 2H),3.62-3.66 (m, 1H), 3.32-3.35 (m, 1H), 3.15-3.20 (m, 1H), 1.57-1.84 (m,6H).

EXAMPLE 1196-(2,5-cis-Dimethyl-1-pyrrolino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 332, Structure 20 of Scheme III, Where R⁴⁻⁷=H, R³═R⁸=Methyl,X=a Double Bond)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV but using2,5-dimethylpyrroline in place of piperidine. Diastereomerically pureCompound 332 was isolated as a yellow solid: R_(f)0.15 (MeOH:CH₂Cl₂,1:19); ¹H NMR (500 MHz, CDCl₃) 11.50-11.70 (bs, 1H), 7.32 (d, J=9.3,1H), 7.07 (s, 1H), 7.02 (dd, J=2.4, 9.3, 1H), 6.91(bs, 1H), 5.83 (s, 2H)4.50 (q, J=5.9, 2H), 1.39 (d, J=6.3, 6H).

EXAMPLE 120(±)-6-(2-Propyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 333, Structure 20 of Scheme III, Where R³=Propyl, R⁴⁻⁸=H,X=CH₂)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and 2-propylpiperidine. Compound 333 wasisolated as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) 12.20-12.40 (bs,1H), 7.35 (d, J=9.3, 1H), 7.31 (dd, J=2.4, 9.3, 1H), 7.16 (s, 1H), 7.07(s, 1H), 4.74-4.78 (m, 1H), 3.28-3.31 (m, 1H), 3.02-3.07 (m, 1H),1.51-1.80 (m, 6H), 1.18-1.42 (m, 4H), 0.86 (t, J=7.3, 3H).

EXAMPLE 121(±)-6-(2-Methoxymethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 334, Structure 20 of Scheme III, Where R³=Methoxymethyl,R⁴⁻⁸=H, X=CH₂)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and 2-methoxymethylpiperidine. Compound 334was isolated as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) 7.43 (dd, J=2.4,9.3, 1H), 7.37 (s, 1H), 7.25-7.30 (m, 1H), 7.11 (s, 1H), 3.80-3.82 (m,2H), 3.74 (s, 3H), 3.64-3.70 (m, 1H), 3.35-3.75 (m, 1H), 3.15-3.21 (m,1H), 1.60-1.90 (m, 6H).

EXAMPLE 122(±)-6-(2-Ethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 335, Structure 20 of Scheme III, Where R³=Ethyl, R⁴⁻⁸=H,X=CH₂)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and 2-ethylpiperidine. Compound 335 wasisolated as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) 11.40-11.60 (bs,1H), 7.29-7.30 (m, 2H), 7.16-7.18 (m, 1H), 7.05 (s, 1H), 3.61-3.65 (m,1H), 3.27-3.30 (m, 1H), 3.02-30.7 (m, 1H), 1.42-1.83 (m, 8H), 0.84 (t,J=7.3, 3H).

EXAMPLE 123 6-(1-Cycloheptylamino)4-trifluoromethyl-2(1H)-quinolinone(Compound 336, Structure 20 of Scheme III, Where R3-8=H, X=—(CH₂)₃—)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and cycloheptylamine. Compound 336 wasisolated as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) 11.20-11:40 (bs,1H), 7.27-7.29 (m, 1H), 7.08 (dd, J=2.4, 9.3, 1H), 7.05 (s, 1H), 6.93(s, 1H), 3.47-3.52 (m, 4H), 1.77-1.81(m, 4H, 1.53-1.62 (m, 4H),1.32-1.36 (m, 2H).

EXAMPLE 124(±)-6-(2-Ethoxycarbonyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 337 Structure 20 of Scheme III, Where R³=Ethoxycarbonyl,R⁴⁻⁸=H, X=—CH₂—)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and ethyl pipecolinate. Compound 337 wasisolated as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) 12.00-12.10 (bs,1H), 7.35 (d, J=9.3, 1H), 7.31(dd, J=2.0, 8.8, 1H), 7.20 (s, 1H), 4.46(dd, J=3.4, 5.4, 1H), 4.07-4.12 (m, 2H), 3.41-3.44 (m, 2H), 2.21-2.25(m, 1H), 1.96-2.03 (m, 1H), 1.87-1.91 (m, 1H), 1.63-1.74 (m, 2H),1.46-1.56 (m, 1H), 1.18 (t, J=7.3, 3H).

EXAMPLE 125(±)-6-(2-Isopropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 338, Structure 20 of Scheme III, Where R³=Isopropyl, R⁴⁻⁸=H,X=a Bond)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and 2-isopropylpyrrolidine. Compound 338was isolated as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) 12.20-12.40 (bs,1H), 7.35 (d, J=9.3, 1H), 7.07 (s, 1H), 7.02 (dd, J=2.4, 9.3, 1H), 6.87(s, 1H), 3.69-3.72 (m, 1H), 3.55-3.59 (m, 1H), 3.23 (q, J=7.8, 1H),2.16-2.19 (m, 1H), 1.92-2.06 (m, 4H), 0.97 (d, J=6.8, 3H), 0.83 (d,J=6.3, 3H).

EXAMPLE 126(±)-6-(2-Hydroxycarbonyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 339, Structure 20 of Scheme III, Where R³=Carboxylic Acid,R⁴⁻⁸=H, X=—CH₂—)

This compound was prepared by hydrolysis of Compound 337 (Structure 20of Scheme III, where R³=ethyl carboxylate, R⁴⁻⁸=H, X=—CH₂—). Compound339 was isolated as a yellow solid: R_(f)=0.23(90:9:1CH₂Cl₂:MeOH:NH₄OH).

EXAMPLE 1276-(3,5-cis-Dimethyl-1-piperazino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 340, Structure 20 of Scheme III, Where R³═R⁴═R⁷═R⁸=H,R⁵═R⁶=Methyl, X=NH)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and 1,6-cis-piperazine. Compound 340 wasisolated as a yellow solid: ¹H NMR (d₆-acetone, 500 MHz) 10.90-1100 (bs,1H), 7.57 (dd, J=2.4, 8.8, 1H), 7.50 (d, J=8.8, 1H), 7.27 (s, 1H), 6.93(s, 1H); 3.87 (d, J=13.2, 2H), 3.69-3.76 (bs, 2H), 3.03 (t, J=11.7, 2H),1.47 (d, J=6.8, 6H).

EXAMPLE 128(±)-6-(2-Benzyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 341, Structure 20 of Scheme III, Where R³=Benzyl,R⁴═R⁵═R⁶═R⁷═R⁸=H, X=a Bond)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and 2-benzylpyrrolidine. Compound 341 wasisolated as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) 10.50-10.60 (bs,1H), 7.31-7.36 (m, 2H), 7.23-7.25 (m, 4H), 7.08 (s, 1H), 7.05 (dd,J=2.4, 8.8, 1H), 7.01 (s, 1H), 3.98-4.02 (m, 1H), 3.48—3.52 (m, 2H),3.25 (q, J=7.8, 1H), 3.07 (dd, J=2.9, 13.7, 1H), 2.57 (dd, J=9.8, 13.7,1H), 1.93-2.01(m, 3H).

EXAMPLE 129(±)-6-(5-Methyl-2-oxo-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 342, Structure 20 of Scheme III, Where R³, R⁴=Carbonyl,R⁵═R⁶═R⁷=H, R⁸=Methyl, X=a Bond)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and 5-methyl-2-pyrrolidinone. Compound 342was isolated as yellow oil: ¹H NMR (CDCl₃, 500 MHz) 12.00-12.40 (bs,1H), 7.77 (dd, J=2.0, 8.8, 1H), 7.73 (s, 1H), 7.48 (d, J=8.8, 1H), 7.12(s, 1H), 4.36 (sextet, J=6.8, 1H), 2.66-2.73 (m, 1H), 2.57-2.64 (m, 1H),2.42-2.48 (m, 1H), 1.80-1.86 (m, 1H), 1.25 (d, J=6.3, 3H).

EXAMPLE 130(±)-6-(2-(2-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 343, Structure 20 of Scheme III, Where R³═R⁴═R⁵═R⁶═R⁷=H,R⁸=2-Hydroxyethyl, X=CH₂)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and2-(2-tert-butyldimethylsilyloxyethyl)piperidine. Compound 343 wasisolated as yellow oil: ¹H NMR (CDCl₃, 500 MHz) 10.80-11.10 (bs, 1H),7.25-7.32 (m, 2H), 7.20 (s, 1H), 7.06 (s, 1H), 4.00-4.07 (m, 2H),3.94-3.99 (m, 1H), 3.32 (d, J=11.9, 1H), 3.04-3.08 (m, 1H), 1.82-1.97(m, 3H), 1.65-1.76 (m, 5H).

EXAMPLE 131(±)-6-(3-Hydroxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 344, Structure 20 of Scheme III, Where R³═R⁴═R⁶═R⁷═R⁸=H,R⁵=Hydroxy, X=a Bond)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and3-tert-butyldimethylsilyloxypyrrolidine. Compound 344 was isolated asyellow solid: ¹H NMR (CDCl₃, 500 MHz) 7.11(d, J=9.3, 1H), 6.07 (dd,J=2.4, 9.3, 1H), 6.78 (s, 1H), 6.60 (s, 1H), 4.39-4.41 (m, 1H),3.33-3.38 (m, 2H), 3.17-3.23 (m, 1H), 3.09 (d, J=10.0, 1H), 1.91-2.03(m, 1H), 1.89-1.86 (m, H).

EXAMPLE 132(±)-6-(3-Acetyloxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 345, Structure 20 of Scheme III, Where R³═R⁴═R⁶═R⁷═R⁸=H,R⁵=Acetyloxy, X=a Bond)

This compound was prepared by acetylation of Compound 131 (Structure 20of Scheme III, where R³═R⁴═R⁶═R⁷═R⁸=H, R⁵=hydroxy, X=a bond) andisolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz), 10.00-10.20 (bs, 1H),7.20-7.21(m, 1H), 7.05 (s, 1H), 6.95 (dd, J=2.7, 9.2, 1H), 6.82 (s, 1H),5.47 (m, 1H), 3.70 (dd, J=2.7, 11.0, 1H), 3.52 (q, J=11.0, 1H), 3.45(dt, J=3.0, 8.5, 1H), 3.40 (d, J=11.0, 1H), 2.23-2.34 (m, 2H), 1.26 (s,3H).

EXAMPLE 1336-(3(R)-Hydroxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 346, Structure 20 of Scheme III, Where R³⁻⁵═R⁷⁻⁸=H,R⁶=Hydroxy, X=a Bond)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and3(R)-(tert-butyldimethylsilyloxy)pyrrolidine. Compound 346 was isolatedas a yellow solid: R_(f)0.36 (MeOH:CH₂Cl₂, 1:9); ¹H NMR (400 MHz, CDCl₃)7.20 (d, J=9.3, 1H), 6.90-7.00 (m, 2H), 6.72 (s, 1H), 4.51-4.56 (m, 1H),3.45-3.49 (m, 2H), 3.20-3.25 (m, 2H), 1.95-2.12 (m, 2H).

EXAMPLE 134 6-(1-Indolino)-4-trifluoromethyl-2(1H)-quinolinone (Compound347, Structure 21 of Scheme III, Where n=0, m=1)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and indoline. Compound 347 was isolated asa yellow solid: ¹H NMR (CDCl₃, 500 MHz) 11.70-11.80 (bs, 1H), 7.58-7.60(m, 2H), 7.42 (d, J=9.3, 1H), 7.22 (d, J=7.3, 1H), 7.07-7.14 (m, 3H),6.81 (dt, J=1.0, 7.3, 1H), 4.02 (t, J=8.3, 2H), 3.20 (t, J=8.3, 2H).

EXAMPLE 1356-(1-Tetrahydroquinolino)-4-trifluoromethyl-2(1H)-quinolinone (Compound348, Structure 21 of Scheme III, Where n=0, m=2)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and 1,2,3,4-tetrahydroquinoline. Compound348 was isolated as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) 11.60-11.80(bs, 1H), 7.61-7.62 (m, 1H), 7.56 (dd, J=2.4, 8.8, 1H), 7.40 (d, J=8.8,1H), 7.08-7.10 (m, 2H), 6.94-6.97 (m, 1H), 6.75-6.78 (m, 1H), 6.70 (t,J=8.3, 1H), 3.68 (t, J=5.6, 2H), 2.88 (t, J=5.6, 2H), 2.05-2.12 (m, 2H).

EXAMPLE 1366-(2-Tetrahydroisoquinolino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 349, Structure 21 of Scheme III, Where n=m=1)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and 1,2,3,4-tetrahydroisoquinoline.Compound 349 was isolated as a yellow solid: ¹H NMR (CDCl₃, 500 MHz)10.80-11.0 (bs, 1H), 7.37 (d, J=2.0, 8.8, 1H), 7.20-7.31(m, 6H), 7.08(s, 1H), 4.44 (s, 2H), 3.60 (t, J=5.9, 2H), 3.04 (t, J=5.9, 2H).

EXAMPLE 137(±)-6-(1,3,3-Trimethyl-6-azabicyclo[3,2,1]octanyl-6-)-4-trifluoromethyl-2(1H)-quinolinone(Compound 350, Structure 22 of Scheme III)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and1,3,3-trimethyl-6-azabicyclo[3.2.1]octane. Compound 350 was isolated asa yellow solid: ¹H NMR (CDCl₃, 500 MHz) 12.40-12.50 (bs, 1H), 7.35 (d,J=9.3, 1H), 7.07 (s, 1H), 6.89 (dd, J=2.4, 9.3, 1H), 6.68 (s, 1H), 4.12(q, J=6.8, 1H), 3.10 (q, J=8.8, 2H), 1.96-1.98 (m, 1H), 1.83-1.86 (m,1H), 1.47-1.60 (m, 2H), 1.43 (d, J=10.7, 1H), 1.35 (d, J=13.6, 1H), 1.18(s, 3H) 0.95 (3H), 0.77 (s, 3H).

EXAMPLE 138(±)-6-(2-Trifluoromethyl-5-cis-methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 351, Structure 25 of Scheme IV, Where R²=Methyl,R³=Trifluoromethyl) and(±)-6-(2-Trifluoromethyl-5-trans-methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 352, Structure 25 of Scheme IV, Where R²=Methyl,R³=Trifluoromethyl)

These compounds were prepared from Compound 200 by the following GeneralProcedure XV (Formation of oxazolidine from amine):

6-(N-1-Hydroxy-2-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 353, Structure 24 of Scheme IV, where R²=methyl):

This compound was prepared in a similar fashion as that described inExample 3, General Procedure V but using 1-hydroxyacetone (Structure 23of Scheme IV, where R²=methyl) in place of acetone.

6-(2-Trifluoromethyl-5-methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compounds 351and 352, Structure 25 of Scheme IV, Where R²=Methyl,R³=trifluoromethyl):

To a solution of Compound 353 in benzene (0.2-0.5 M) was addedtrifluoroacetaldehyde monohydrate or ethyl hemiacetal (3-5 equiv) in thepresence of p-toluenesulfonic acid (2-10 mol %). The reaction mixturewas refluxed for 5-15 h with azeotropic removal of water with aDean-Stark condenser. The mixture was diluted with EtOAc and washed with2 M NaHCO₃, and condensed. Chromatography afforded the desired products.

Compound 351 was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃)12.1(bs, 1H), 7.42 (d, =9.3, 1H), 7.20 (s, 1H), 7.17 (d, J=9.3, 1H),7.11 (s, 1H), 5.32 (q, J_(H-F)=4.9, 1H), 4.46 (dd, J=8.3, 6.8, 1H),4.11-4.04 (m, 1H), 3.99 (dd, J=8.3, 8.3, 1H), 1.42 (d, J=5.9, 3H).

Compound 352 was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃)12.1 (bs, 1H), 7.40 (d, J=9.3, 1H),7.17 (d, J=9.3, 1H),7.14 (s, 1H),7.11 (s, 1H), 5.55 (q, J_(H-F)=4.4, 1H), 4.46 (dd, J=8.3, 2.4, 1H),4.33-4.30 (m, 1H), 3.99 (d, J=8.3, 1H), 1.19 (d, J=6.3, 3H).

EXAMPLE 139(±)-6-(2-Trifluoromethyl-5-cis-ethyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 354, Structure 25 of Scheme IV, Where R²=Ethyl,R³=Trifluoromethyl) and(±)-6-(2-Trifluoromethyl-5-trans-ethyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 355, Structure 25 of Scheme IV, Where R²=Ethyl,R³=Trifluoromethyl)

These compounds were prepared in a similar fashion as that described inExample 138, General Procedure XV but using 1-hydroxy-2-butanone(Structure 23 of Scheme IV, where R²=ethyl) in the place of1-hydroxyacetone.

Compound 354 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)12.7 (bs, 1H), 7.46 (d, J=8.8, 1H), 7.20 (s, 1H), 7.18 (d, J=8.8, 1H),7.11 (s, 1H), 5.31 (q, J_(H-F)=4.9, 1H), 4.44 (dd, J=7.8, 7.2, 1H), 4.06(dd, J=7.8, 7.4, 1H), 3.86-3.82 (m, 1H), 2.04-1.96 (m, 1H), 1.66-1.59(m, 1H), 0.99 (t, J=7.3, 3H).

Compound 355 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)12.0 (bs, 1H), 7.38 (d, J=8.8, 1H), 7.15 (d, J=8.8, 1H), 7.12 (s, 1H),7.10 (s, 1H), 5.56 (q, J_(H-F)=4.4, 1H), 4.42 (dd, J=7.3, 6.8, 1H),4.13-4.09 (m, 2H), 1.74-1.66 (m, 1H), 1.52-1.43 (m, 1H), 0.86 (t, J=7.3,3H).

EXAMPLE 140(±)-6-(5-Methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 356, Structure 25 of Scheme IV, Where R²=Methyl, R³=H)

These compounds were prepared in a similar fashion as that described inExample 138, General Procedure XV but using formaldehyde in the place oftrifluoroacetaldehyde. Compound 356 was isolated as a yellow solid: ¹HNMR (500 MHz, CDCl₃) 11.9 (bs, 1H), 7.36 (d, J=8.8, 1H), 7.09 (s, 1H),6.91 (dd, J=8.8, 2.4, 1H), 6.81 (s, 1H), 5.05 (d, J=2.4, 1H), 4.84 (d,J=2.4, 1H), 4.19 (dd, J=8.3, 3.4, 1H), 3.96-3.93 (m, 1H), 3.85 (dd,J=8.3, 3.4, 1H), 1.31 (d, J=5.9, 3H).

EXAMPLE 1416-(2,5-Dimethyl-1-pyrrolyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 357, Structure 20 of Scheme IV, Where R³═R⁸=Methyl, R⁴, R⁵=aBond, R⁷, R⁸=a Bond, X=a Bond)

To PhH (2.5 mL) and AcOH (0.7 mL) was added Compound 200 (Structure 3 ofScheme IV) (23 mg, 0.10 mmol) and acetonylacetone (Structure 28 ofScheme IV, where R²═R³=methyl, X=a bond) (14 mg, 0.12 mmol) and thereaction mixture refluxed for 4.5 h while removing water with aDean-Stark trap. The cooled reaction mixture was diluted with EtOAc andwashed successively with 2M HCl, satd. NaHCO₃, and brine. The organiclayers were dried over MgSO₄, concentrated in vacuo, and chromatographedtwice (MeOH:CH₂Cl₂, 1:9, then gradient of CH₂Cl₂ to MeOH:CH₂Cl₂, 1:9) toproduce 18.0 mg (58%) of Compound 357 as a yellow solid: R_(f)0.20(MeOH:CH₂Cl₂, 1:9); ¹H NMR (500 MHz, CDCl₃) 11.00-11.20 (bs, 1H), 7.73(s, 1H), 7.46-7.48 (m, 2H), 7.16 (s, 1H), 5.96 (s, 2H), 2.06 (s, 6H).

EXAMPLE 1426-N-2,2,2-Trifluoroethyl-N-3,3,3-trifluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 358, Structure 7 of Scheme IV, Where R²=2,2,2-Trifluoroethyl,R¹=3,3,3-Trifluoropropyl)

6-Amino-4-trifluoromethyl-2-isopropyloxyquinoline (Compound 359,Structure 26 of Scheme IV):

This compound was prepared from Compound 200 (Structure 3 of Scheme IV)in a similar fashion as that described in Example 101, General ProcedureXII.

6-(N-3,3,3-Trifluoropropyl)amino-4-trifluoromethyl-2-isopropyloxyquinoline(Compound 360, Structure 26 of Scheme IV):

A mixture of Compound 359, 3,3,3-trifluoro-1-iodopropane and K₂CO₃ inDMF was heated at 100° C. for 2h and was quenched with water. Extractionwith EtOAc, washing with brine and removal of solvent followed bychromatography afforded Compound 360 as yellow oil.

6-(N-2,2,2-Trifluoroethyl-N-3,3,3-trifluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 358, Structure 7 of Scheme IV, where R²=2,2,2-trifluoroethyl,R³=3,3,3-trifluoropropyl):

This compound was prepared from Compound 360 by reductive alkylation andacidic hydrolysis in similar fashion as that described in Example 2,General Procedure IV and Example 101, General Procedure XIV. Compound358 was isolated as yellow solid. ¹H NMR (400 MHz, acetone-d₆) 10.90 (s,1H), 7.50 (d, J=9.2, 1H), 7.43 (dd, J=9.2, 2.5, 1H), 7.16 (s, 1H), 6.93(s, 1H), 4.28 (q, J=9.2, 2H), 3.88-3.84 (m, 2H), 2.75-2.60 (m, 2H).

EXAMPLE 1436-bis-N,N-Thiomethoxymethylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 361, Structure 7 of Scheme IV, Where R¹═R²=Thiomethoxymethyl)and6-bis-N,N-Thiomethoxymethylamino-4-trifluoromethyl-2-thiomethoxymethyloxyquinoline(Compound 362, Structure 27 of Scheme IV)

To a solution of Compound 200 (Structure 3 of Scheme IV) in THF wasadded NaH and chloromethyl methyl sulfide and the reaction mixture wasstirred at rt for 1 h and quenched with water. Extraction with EtOAc,washing with brine, removal of solvent and chromatography affordedCompounds 361 and 362.

Compound 361 was isolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz)7.36-7.38 (m, 3H), 7.08 (s, 1H), 5.40 -5.50 (bs, 2H), 4.67 (s, 4H), 2.29(s, 3H), 2.17 (s, 6H).

Compound 362 was isolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz)11.80-12.00 (bs, 1H), 7.32-7.36 (m, 3H), 7.09 (s, 1H), 4.67 (s, 4H),2.16 (t, J=20.5, 6H).

EXAMPLE 144(±)-6-(2,5-trans-Diethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 363, Structure 20 of Scheme IV, Where R²═R⁸=Ethyl,R⁴═R⁵═R⁶═R⁷=H, X=a Bond) and6-(2,5-cis-Diethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 364, Structure 20 of Scheme IV, Where R²═R⁸=Ethyl,R⁴═R⁵═R⁶═R⁷=H, X=a Bond)

These compounds were prepared by the following General Procedure XVI:

To a mixture of Compound 200 (Structure 3 of Scheme IV), acetic acid(10% equiv) and KOH (25% equiv) in methanol was added a diketone (2-5equiv) and a reducing agent such as Na(CN)BH₃. The mixture was stirredat elevated temperature till the products were formed by TLC andquenched with water. Removal of solvent and chromatography of the cruderesidue afforded the pyrrolidinyl compounds in moderate yield.

Compound 363 was isolated as a major product: ¹H NMR (500 MHz, CDCl₃)7.23 (d, J=8.5, 1H), 6.99 (s, 1H), 6.91 (dd, J=8.5, 2.5, 1H), 6.74 (s,1H), 3.69 (t, J=7.5, 2H), 1.73-1.70 (m, 2H), 1.81(d, J=5.0, 1H),1.73-1.69 (m, 2H), 1.18-1.15 (m, 2H), 0.91(t, J=7.5, 6H).

Compound 364 was isolated as a minor product: ¹H NMR (500MHz CDCl₃) 7.20(d, J=9.0, 1H), 6.99 (s, 1H), 6.97 (dd, J=9.0, 2.4, 1H), 6.84 (m, 1H),3.54 (m, 2H), 2.08-2.00 (m, 2H), 1.90-1.78 (m, 4H), 1.42-1.33 (m, 2H),0.97 (t, J=7.5, 6H).

EXAMPLE 145(±)-6-(2,5-trans-Dipropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 365, Structure 20 of Scheme IV, Where R³═R⁸=Propyl,R⁴═R⁵═R⁶═R⁷=H, X=a Bond),6-(2,5-cis-Dipropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 366, Structure 20 of Scheme IV, Where R³═R⁸=Propyl,R⁴═R⁵═R⁶═R⁷=H, X=a Bond) and6-(2,5-Dipropyl-1-pyrrolo)-4-trifluoromethyl-2(1H)-quinolinone (Compound367, Structure 20 of Scheme IV, where R³═R⁸=Propyl, R⁴, R⁵═R⁶, R⁷═X=aBond)

These compounds were prepared from Compound 200 (Structure 3 of SchemeIV) and 4,7-decanedione by General Procedure XVI described in Example144.

Compound 365 was isolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz)11.20-11.30 (bs, 1H), 7.23-7.31(m, 1H), 7.04 (s, 1H), 6.92 (dd, J=2.4,8.8, 1H) 6.76 (s, 1H), 3.77 (t, J=7.8, 2H), 2.09-2.14 (m, 2H), 1.80-1.84(m, 2H), 1.61-1.68 (m, 2H), 1.26-1.57 (m, 4H), 0.99-1.17 (m, 2H), 0.95(t, J=7.3, 6H).

Compound 366 was isolated as yellow oil: ¹H NMR (CDCl₃, 500 MHz)10.60-10.70 (bs, 1H), 7.22 (d, J=9.3, 1H), 7.03 (s, 1H), 6.97 (dd,J=2.9, 9.3, 1H), 6.86 (s, 1H), 3.60-3.68 (m, 2H), 2.00-2.18 (m, 2H),1.77-1.83 (m, 4H), 1.31-1.47 (m, 6H), 1.00 (t, J=7.3, 6H).

Compound 367 was isolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz)12.60-12.80 (bs, 1H), 7.75 (s, 1H), 7.61 (d, J=8.3, 1H), 7.51 (dd,J=2.4, 8.8, 1H), 7.19 (s, 1H), 6.00 (s, 2H), 2.30 (t, J=7.3, 4H), 1.51(sextet, J=7.8, 4H), 0.85 (t, J=7.3, 6H).

EXAMPLE 146(±)-6-(2,5-trans-Dibutyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 369, Structure 20 of Scheme IV, Where R³═R⁸=Butyl,R⁴═R⁵═R⁶═R⁷=H, X=a Bond) and6-(2,5-cis-Dibutyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 368, Structure 20 of Scheme IV, Where R³═R⁸=Butyl,R⁴═R⁵═R⁶═R⁷=H, X=a Bond)

These compounds were prepared from Compound 200 (Structure 3 of SchemeIV) and 5,8-dodecanedione by General Procedure XVI described in Example144.

Compound 369 was isolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz)9.80-10.00 (bs, 1H), 7.15 (d, J=8.8, 1H), 7.06 (s, 1H), 6.89 (dd, J=2.4,9.3, 1H), 6.75 (s, 1H), 3.73-3.75 (m, 2H), 2.04-2.13 (m,2H), 1.80-1.88(m, 2H), 1.60-1.69 (m, 2H), 1.26-1.48 (m, 8H), 0.89-0.94 (m, 6H).

Compound 368 was isolated as yellow oil: ¹H NMR (CDCl₃, 500 MHz)9.40-9.60 (bs, 1H), 7.12 (d, J=8.8, 1H), 7.01 (s, 1H), 6.94-6.95 (m,1H), 6.85 (s, 1H), 3.56-3.64 (m, 2H), 2.00-2.05 (m, 2H), 1.81-1.90 (m,4H), 1.26-1.48 (m, 1H), 0.95 (t, J=6.3, 6H).

EXAMPLE 147(±)-6-(2,6-trans-Diethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 371, Structure 20 of Scheme IV, Where R³═R⁸=Ethyl,R⁴═R⁵═R⁶═R⁷=H, X=CH₂) and6-(2,6-cis-Diethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 370, Structure 20 of Scheme IV, Where R³═R⁸=Ethyl,R⁴═R⁵═R⁶═R⁷=H, X=CH₂)

These compounds were prepared from Compound 200 (Structure 3 of SchemeIV) and 3,7-nonanedione by General Procedure XVI described in Example144.

Compound 371 was isolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz)11.40-11.60 (bs, 1H), 7.27-7.31 (m, 3H), 7.06 (s, 1H), 3.24-3.26 (m,2H), 1.85-1.89 (m, 2H), 1.50-1.59 (m, 4H), 1.48-1.50 (m, 2H), 1.38-1.48(m, 2H), 0.77 (t, J=7.3, 6H).

Compound 370 was isolated as yellow solid: ¹H NMR (CDCl₃, 500 MHz)11.20-11.40 (bs, 1H), 7.31-7.36 (m, 3H), 7.06 (s, 1H), 3.09-3.12 (m,2H), 1.77-1.81 (m, 2H), 1.49-1.53 (m, 2H), 1.23-1.39 (m, 6H), 0.82 (t,J=7.3, 6H).

EXAMPLE 148(±)-6-(2,6-trans-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 373, Structure 20 of Scheme IV, Where R³═R⁸=Methyl,R⁴═R⁵═R⁶═R⁷=H, X=CH₂) and6-(2,6-cis-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 372, Structure 20 of Scheme IV, Where R³═R⁸=Methyl,R⁴═R⁵═R⁶═R⁷=H, X=CH₂)

These compounds were prepared from Compound 200 (Structure 3 of SchemeIV) and 2,6-heptanedione by General Procedure XVI described in Example144.

Compound 373 was isolated as yellow solid. ¹H NMR (500 MHz, CDCl₃) 11.88(bs, 1H), 7.38-7.36 (m, 3H), 7.08 (s, 1H), 3.52 (q, J=6.3, 2H),1.97-1.90 (m, 2H), 1.68-1.51(m, 4H), 0.93 (d, J=5.9, 6H).

Compound 372 was isolated as yellow solid: ¹H NMR (CDCl₃, 500 MHz)12.00-12,20 (bs, 1H), 7.58 (bs, 1H), 7.47 (dd, J=2.0, 8.8, 1H), 7.42(dd, J=1.0, 8.8, 1H), 7.10 (s, 1H), 2.91-2.96 (m, 2H), 1.76-1.84 (m,3H), 1.52-1.57 (m, 1H), 1.41-1.48 (m, 2H), 0.77 (d, J=6.3, 6H).

EXAMPLE 1496-(N-Propyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 374, Structure 31 of Scheme V, Where R=Methyl, R¹═R²═R³═R⁴=H,R⁵=Propyl, R⁶=2,2,2-Trifluoroethyl)

6-Amino-4-methyl-2(1H)-quinolinone (Compound 375, Structure 30 of SchemeV, where R=methyl, R¹═R²═R³═R⁴=H)

This compound was prepared in a similar fashion as that described inExample 1, General Procedures II and III but using4-methyl-2(1H)-quinolinone (Compound 376, Structure 29 of Scheme V,where R=methyl, R¹═R²═R³═R⁴=H) in place of Compound 202. Compound 375was isolated as a solid: R_(f)0.26 (MeOH:CH₂Cl₂, 1:9); ¹H NMR (500 MHz,CD₃OD) 7.19 (d, J=8.8, 1H), 7.08 (d, J=2.4, 1H), 7.04 (dd, J=2.4, 8.8,1H), 6.47 (s, 1H), 2.47 (s, 3H).

6-(N-Propyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 374, Structure 31 of Scheme V, where R=methyl, R¹═R²═R³=R⁴H,R⁵=propyl, R⁶=2,2,2-trifluoroethyl):

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI to install trifluoroethyl by usingtrifluoroacetic acid and Example 2, General Procedure IV to install thepropyl. Compound 374 was isolated as a solid: R_(f)0.53 (MeOH:CH₂Cl₂,1:19); ¹H NMR (500 MHz, CDCl₃) 10.20-10.30 (bs, 1H); 7.18 (d, J=8.9,1H), 7.00-7.07 (m, 1H), 6.97 (dd, J=2.4, 9.3, 1H), 6.55 (s, 1H), 3.89(q, J=8.9, 2H), 3.39 (t, J=7.8, 2H), 2.46 (s, 3H), 1.64-1.67 (m, 2H),0.96 (t, J=7.4, 3H).

EXAMPLE 150 6-(bis-2,2,2-Trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 377, Structure 31 of Scheme V, Where R=Methyl, R¹═R²═R³═R⁴=H,R⁵═R⁶=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using Compound 375 (Structure 30of Scheme V, where R=methyl, R¹═R²═R³═R⁴=H) in place of Compound 200.Compound 377 was isolated as a yellow solid: R_(f)0.40 (MeOH:CH₂Cl₂,1:9); ¹H NMR (500 MHz, CDCl₃) 10.80-11.00 (bs, 1H), 7.16-7.25 (m, 3H),6.56 (bs, 1H), 4.06 (q, J=8.5, 4H), 2.45 (s, 3H).

EXAMPLE 151 6-(2,5-Dimethyl-1-pyrrolo)-4-methyl-2(1H)-quinolinone(Compound 378, Structure 20a of Scheme V, R⁴, R⁵=R⁶, R⁷=a Bond,R³═R⁸=Methyl, X=a Bond),(±)-6-(2,5-trans-Dimethyl-1-pyrrolidino)-4-methyl-2(1H)-quinolinone(Compound 379, Structure 20a of Scheme V, R³═R⁸=Methyl, R⁴═R⁵═R⁶═R⁷=H,X=a Bond) and6-(2,5-cis-Dimethyl-1-pyrrolidino)-4-methyl-2(1H)-quinolinone (Compound380, Structure 20a of Scheme V, R³═R⁸=Methyl, R⁴═R⁵═R⁶═R⁷=H, X=a Bond)

These compounds were prepared in a similar fashion as that described inExample 144, General Procedure XVI but using Compound 375 (Structure 30of Scheme V, where R=methyl, R¹═R²═R³═R⁴=H) in place of Compound 200.

Compound 378 was isolated as a yellow solid: R_(f)0.52 (MeOH:CH₂Cl₂,1:9); ¹H NMR (400 MHz, CDCl₃) 10.60-10.80 (bs, 1H), 7.54 (s, 1H), 7.37(s, 2H), 6.63 (s, 1H), 5.94 (s, 2H), 2.48 (s, 3H), 2.04 (s, 6H).

Compound 379 was isolated as yellow solid. ¹H NMR (400 MHz, CDCl₃) 11.15(bs, 1H), 7.22 (d, J=8.9, 1H), 6.90 (dd, J=8.9, 2.5, 1H), 6.68 (d,J=2.5, 1H), 6.54 (s, 1H), 4.06(t, J=6.3, 2H), 2.45 (s, 3H), 2,27 (m,2H), 1.67 (m, 2H), 1.13 (s, 3H), 1.11 (s, 3H).

Compound 380 was isolated as yellow solid. ¹H NMR (400 MHz, CDCl₃) 10.48(bs, 1H), 7.17 (d, J=8.9, 1H), 6.93 (dd, J=8.9, 2.5, 1H), 6.74 (d,J=2.5, 1H), 6.53 (s, 1H), 3.78 (m, 2H), 2.46 (s, 3H), 2.09 (m, 2H), 1.76(m, 2H), 1.32 (s, 3H), 1.31(s, 3H).

EXAMPLE 1526-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 381, Structure 31 of Scheme V, Where R=Methyl, R¹═R²═R³═R⁴=H,R⁵=Isobutyl, R⁶=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 375 (Structure 30 of Scheme V,where R=methyl, R¹═R²═R³═R⁴=H) in a similar fashion as that described inExample 9, General Procedure VI to install trifluoroethyl fromtrifluoroacetic acid and Example 2, General Procedure IV to install theisobutyl. Compound 381was isolated as a solid: R_(f)0.18 (MeOH:CH₂Cl₂,3:7); ¹H NMR (500 MHz, CDCl₃) 11.80-12.00 (bs, 1H), 7.32 (d, J=9.3, 1H),7.12 (dd, J=2.4, 9.3, 1H), 7.02 (d, J=2.9, 1H), 6.56 (s, 1H), 3.92 (q,J=8.8, 2H), 3.23 (d, J=7.3, 2H), 2.47 (s, 3H), 2.04 (quin, J=6.8, 1H),0.95 (d J=6.8, 6H).

EXAMPLE 1536-(N-2,2,2-Chlorodifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 382, Structure 31 of Scheme V, Where R=MethylR¹═R²═R³═R⁴═R⁵=H, R⁶=2,2,2-Chlorodifluoroethyl)

This compound was prepared from Compound 375 (Structure 30 of Scheme V,where R=methyl, R¹═R²═R³═R⁴=H) and chlorodifluoroacetic acid in asimilar fashion as that described in Example 9, General Procedure VI.Compound 382 was isolated as a solid: ¹H NMR (CDCl₃) 10.28 (bs, 1H),7.15 (d, J=8.6, 1H), 7.10 (d, J=8.6, 1H), 6.91 (s, 1H), 6.54 (s, 1H),4.13 (t, J=7.2, 1H), 3.95 (m, 2H), 2.45 (s, 3H).

EXAMPLE 1546-(bis-N,N-2,2,2-Chlorodifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 383, Structure 31 of Scheme V, Where R=Methyl, R¹═R²═R³═R⁴=H,R⁵═R⁶=2,2,2-Chlorodifluoroethyl)

This compound was prepared from Compound 375 (Structure 30 of Scheme V,where R=methyl, R¹═R²═R³═R⁴=H) and chlorodifluoroacetic acid in asimilar fashion as that described in Example 9, General Procedure VI.Compound 383 was isolated as a solid: ¹H NMR (CDCl₃) 11.50 (bs, 1H),7.35 (d, J=9.7, 1H), 7.25-7.23 (m, 2H), 6.59 (s, 1H), 4.24 (t, J=12.0,4H), 2.49 (s, 3H).

EXAMPLE 1556-(N-2,2,2-Chlorodifluoroethyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 384, Structure 31 of Scheme V, Where R=Methyl, R¹═R²═R³═R⁴=H,R⁵=2,2,2-Trifluoroethyl, R⁶=2,2,2-Chlorodifluoroethyl)

This compound was prepared from Compound 375 (Structure 30 of Scheme V,where R=methyl, R¹═R²═R³═R⁴=H) in a similar fashion as that described inExample 9, General Procedure VI using chlorodifluoroacetic acid andtrifluoroacetic acid sequentially. Compound 384 was isolated as a solid:¹H NMR (CDCl₃) 11.33 (bs, 1H), 7.37 (d, J=8.5, 1H), 7.23 (d, J=8.5, 1H),7.20 (s, 1H), 4.20 (t, J=11.7, 2H), 4.09 (q, J=8.5, 2H), 2.48 (s, 3H).

EXAMPLE 156 6-N-Ethylamino-4-methyl-2(1H)-quinolinone (Compound 385,Structure 31 of Scheme V, Where R=Methyl, R¹═R²═R³═R⁴═R⁵=H, R⁶=Ethyl)

This compound was prepared from Compound 375 (Structure 30 of Scheme V,where R=methyl, R¹═R²═R³═R⁴=H) in a similar fashion as that described inExample 9, General Procedure VI using acetic acid. Compound 385 wasisolated as a solid: ¹H NMR (CDCl₃) 11.05 (bs, 1H), 7.23 (d, J=8.7, 1H),6.87 (dd, J=8.7, 2.6, 1H), 6.75 (s, 1H), 6.54 (s, 1H), 3.65 (bs, 1H),3.21 (q, J=7.1, 2H), 2.45 (s, 3H), 1.30 (t, J=7.1, 3H).

EXAMPLE 1576-(N-Ethyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 386, Structure 31 of Scheme V, Where R=Methyl, R¹═R²═R³═R⁴=H,R⁵=2,2,2-Trifluoroethyl, R⁶=Ethyl)

This compound was prepared from Compound 375 (Structure 30 of Scheme V,where R=methyl, R¹═R²═R³═R⁴=H) in a similar fashion as that described inExample 9, General Procedure VI using acetic acid and trifluoroaceticacid sequentially. Compound 386 was isolated as a solid: ¹H NMR (CDCl₃)11.23 (bs, 1H), 7.36 (d, J=8.9, 1H), 7.08 (dd, J=9.0, 2.5, 1H), 6.98 (d,J=2.5, 1H), 6.58 (s, 1H), 3.87 (q, J=9.0, 2H), 3.52 (q, J=7.0, 2H), 2.48(s, 3H), 1.22 (t, J=7.0, 3H).

EXAMPLE 158 6-N,N-Diethylamino-4-methyl-2(1H)-quinolinone (Compound 387,Structure 31 of Scheme V, Where R=Methyl, R¹═R²═R³═R⁴═R⁵=H, R⁶=Ethyl)

This compound was prepared from Compound 375 (Structure 30 of Scheme V,where R=methyl, R¹═R²═R³═R⁴=H) and acetic acid in a similar fashion asthat described in Example 9, General Procedure VI. Compound 387 wasisolated as a solid: ¹H NMR (CDCl₃) 11.72 (bs, 1H), 7.29 (d, J=8.9, 1H),7.02 (dd, J=11.6, 2.6, 1H), 6.83 (d, J=2.6, 1H), 6.55 (s, 1H), 3.38 (q,J=7.0, 4H), 2.47 (s, 3), 1.17 (t, J=7.0, 6H).

EXAMPLE 159 6-(bis-2,2,2-Trifluoroethyl)amino-4-ethyl-2(1H)-quinolinone(Compound 388, Structure 31 of Scheme V, Where R=Ethyl, R¹═R²═R³═R⁴=H,R⁵═R⁶=2,2,2-Trifluoroethyl)

6-Amino-4-ethyl-2(1H)-quinolinone (Compound 389, Structure 30 of SchemeV, where R=ethyl, R¹═R²═R³═R⁴=H):

This compound was prepared in a similar fashion as that described inExample 1, General Procedures II and III but using4-ethyl-2(1H)-quinolinone (Compound 390, Structure 29 of Scheme V, whereR=ethyl, R¹═R²═R³═R⁴=H) in place of Compound 202. Compound 389 wasisolated as a solid: R_(f)0.42 (MeOH:CH₂Cl₂, 1:9; ¹H NMR (500 MHz,CD₃OD) 7.20 (d, J=8.8, 1H), 7.13 (d, J=2.4, 1H), 7.04 (dd, J=2.4, 8.8,1H), 6.47 (s, 1H), 2.88 (q, J=7.3, 2H), 1.34 (t, J=7.3, 3H).

6-(bis-2,2,2-trifluoroethyl)amino-4-ethyl-2(1H)-quinolinone (Compound388, Structure 31 of Scheme V, where R=ethyl, R¹═R²═R³═R⁴=H,R⁵═R⁶=2,2,2-trifluoroethyl):

This compound was prepared from Compound 389 in a similar fashion asthat described in Example 9, General Procedure VI to installtrifluoroethyl from trifluoroacetic acid. Compound 388 was isolated as asolid: R_(f)0.53 (MeOH:CH₂Cl₂, 1:9); ¹H NMR (500 MHz, CDCl₃) 12.20-12.40(bs, 1H), 7.41 (d, J=9.3, 1H), 7.25 (d, J=2.4, 1H), 7.20 (dd, J=2.4,9.3, 1H), 6.62 (s, 1H), 4.05 (q, J=8.8, 4H), 2.85 (q, J=7.3, 2H) 1.35(t, J=7.3, 3H).

EXAMPLE 1606-(bis-2,2,2-Trifluoroethyl)amino-4-isopropyl-2(1H)-quinolinone(Compound 391, Structure 31of Scheme V, Where R=Isopropyl,R¹═R²═R³═R⁴=H, R⁵═R⁶=2,2,2-Trifluoroethyl)

6-Amino-4-isopropyl-2(1H)-quinolinone (Compound 392, Structure 30 ofScheme V, where R=isopropyl, R¹═R²═R³═R⁴=H):

This compound was prepared in a similar fashion as that described inExample 1, General Procedures II and III but using4-isopropyl-2(1H)-quinolinone (Structure 29 of Scheme V, whereR=isopropyl, R¹═R²═R³═R⁴=H) in place of Compound 202.

6-(bis-2,2,2-trifluoroethyl)amino-4-isopropyl-2(1H)-quinolinone(Compound 391, Structure 31 of Scheme V, where R=isopropyl,R¹═R²═R³═R⁴=H, R⁵═R⁶=2,2,2-trifluoroethyl):

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 391and trifluoroaceticacid as a yellow solid. ¹H NMR (CDCl₃) 11.22 (bs, 1H), 7.42 (d, J=8.9,1H), 7.27 (s, 1H), 7.18 (dd, J=8.9, 2.3, 1H), 6.65 (s, 1H), 4.04 (q,J=8.5, 4H), 3.30 (quin, J=6.7, 1H), 1.29 (d, J=6.7, 6H).

EXAMPLE 1617-Fluoro-6-(bis-N,N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 393, Structure 31 of Scheme V, Where R=Trifluoromethyl,R¹═R²═R⁴=H, R³=Fluoro, R⁵═R⁶=2,2,2-Trifluoroethyl)

7-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 394, Structure 29of Scheme V) V, where R=trifluoromethyl, R¹═R²═R⁴=H, R³=fluoro)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 3-fluoroaniline in place ofaniline. Compound 394 was isolated as a yellow solid: ¹H NMR (400 MHz,acetone-d₆) 11.30 (s, 1H), 7.87-7.85 (m, 1H), 7.27 (dd, J=2.5, 9.8, 1H),7.16 (dt, J=2.5, 8.9, 1H), 6.92 (s, 1H).

5-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 395, Structure 29of Scheme V, where R=trifluoromethyl, R¹═R³═R⁴=H, R²=fluoro)

This compound was isolated as a by-product: ¹H NMR (400 MHz, acetone-d₆)11.32 (s, 1H), 7.70-7.65 (m, 1H), 7.38 (d, J=8.5, 1H) 7.12-7.07 (m, 1H),7.04 (s, 1H).

6-Amino-7-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 396,Structure 30 of Scheme V, where R=trifluoromethyl, R¹═R²═R⁴=H,R³=fluoro):

This compound was prepared in a similar fashion as that described inExample 1, General Procedures II and III but using Compound 394 in placeof Compound 202. Compound 396 was isolated as a yellow solid.

7-Fluoro-6-(bis-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 393, Structure 31 of Scheme V, where R=trifluoromethyl,R¹═R²═R⁴=H, R³=fluoro, R⁵═R⁶=2,2,2-trifluoroethyl):

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI to install trifluoroethyl fromtrifluoroacetic acid but using Compound 396 in place of Compound 200.Compound 393 was isolated as a yellow solid: ¹H NMR (400 MHz,acetone-d₆) 11.28 (s, 1H), 7.79 (d, J=8.2, 1H), 7.34 (d, J=12.0, 1H),6.94 (s, 1H), 4.45 (q, J=8.7, 4H).

EXAMPLE 1628-Fluoro-6-(bis-N,N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 397, Structure 31 of Scheme V, Where R=Trifluoromethyl,R¹═R²═R³=H, R⁴=Fluoro, R⁵═R⁶=2,2,2-Trifluoroethyl)

8-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 398, Structure 29of Scheme V, where R=trifluoromethyl, R¹═R²═R³=H, R⁴=fluoro)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 2-fluoroaniline in place ofaniline. Compound 398 was isolated as a yellow solid: ¹H NMR (400 MHz,acetone-d₆) 11.04 (s, 1H), 7.62 (d, J=8.7, 1H), 7.535-7.50 (m, 1H),7.37-7.32 (m, 1H), 7.02 (s, 1H).

6-Amino-8-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 399,Structure 30 of Scheme V, where R=trifluoromethyl, R¹═R²═R³=H,R⁴=fluoro):

This compound was prepared in a similar fashion as that described inExample 1, General Procedures II and III but using Compound 398 in placeof Compound 202. Compound 399 was isolated as a yellow solid: ¹H NMR(400 MHz, acetone-d₆) 11.25 (s, 1H), 6.97 (dd, J=2.2, 12.6, 1H), 6.96(s, 1H), 6.87-6.86 (m, 1H), 5.16 (s, 2H).

8-Fluoro-6-(N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 400, Structure 31 of Scheme V, where R=trifluoromethyl,R¹═R²═R³═R⁶=H, R⁴=fluoro, R⁵=2,2,2-trifluoroethyl):

This compound was prepared in a similar fashion as those described inExample 9, General Procedure VI but using Compound 399 in place ofCompound 200. Compound 400 was isolated as a yellow solid: ¹H NMR,(400MHz, acetone-d₆) 10.88 (s, 1H), 7.15 (dd, J=12.9, 2,2, 1H), 6.97 (s,1H), 6.95 (d, J=9.9, 1H), 6.07 (s, 1H), 4.09-4.02 (m, 2H).

8-Fluoro-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 397, Structure 31 of Scheme V, where R=trifluoromethyl,R¹═R²═R³=H, R⁴=fluoro, R⁵═R⁶=2,2,2-trifluoroethyl):

This compound was prepared in a similar fashion as those described inExample 9, General Procedure VI but using Compound 399 in place ofCompound 200 and excess of NaBH₄. Compound 397 was isolated as a yellowsolid: ¹H NMR (400 MHz, acetone-d₆) 11.07 (s, 1H), 7.54 (dd, J=2.5,13.5, 1H), 7.17 (s, 1H), 7.03 (s, 1H), 4.45 (q, J=8.7, 4H).

EXAMPLE 1638-Fluoro-6-(N-2,2,2-trifluoroethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 401, Structure 31 of Scheme V, Where R=Trifluoromethyl,R¹═R²═R³=H, R⁴=Fluoro, R⁵=2,2,2-Trifluoroethyl, R⁶=Isopropyl)

This compound was prepared in a similar fashion as those described inExample 15, General Procedure VIII but using Compound 400 and acetone inplace of Compound 200. Compound 401was isolated as a yellow solid: ¹HNMR (400 MHz, acetone-d₆) 11.50 (s, 1H), 7.46 (d, J=2.5, 1H), 7.09 (s,1H), 7.00 (s, 1H), 4.09 (q, J=8.5, 2H), 2.09-2.02 (m, 1H), 1.26 (d,J=7.0, 6H).

EXAMPLE 164 6-Amino-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone(Compound 402, Structure 30 of Scheme V, Where R=Trifluoromethyl,R²═R³═R⁴=H, R¹=Fluoro)

This compound was prepared in a similar fashion as that described inExample 1, General Procedures I, II and III but using ethyl2,4,4,4-tetrafluoroacetoacetate in place of ethyl4,4,4-trifluoroacetoacetate. Compound 402 was isolated as a yellowsolid: ¹H NMR (400 MHz, DMSO-d₆) 12.48 (s, 1H), 7.16 (d, J=8.7, 1H),6.92 (dd, J=2,2, 8.8, 1H), 6.89 (d, J=2,2, 1H), 5.36 (bs, 1H).

EXAMPLE 1653-Fluoro-6-(2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 403, Structure 31 of Scheme V, Where R=Trifluoromethyl,R²═R³═R⁴=H, R¹=Fluoro) R⁵=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 402 (Structure 30 ofScheme V, where R=trifluoromethyl, R²═R³═R⁴=H, R¹=fluoro) and TFA inplace of Compound 200 and difluoroacetic acid. Compound 403 was isolatedas a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) 12.55 (s, 1H), 7.26 (d,J=9.1, 1H), 7.15 (dd, J=2.1, 9.1, 1H), 6.98 (d, J=2.1, 1H), 6.54 (t,J=6.8, 1H), 3.95 (m, 2H).

EXAMPLE 1663-Fluoro-6-(bis-2,2,2-trifluorofluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 404, Structure 22 of Scheme V, Where R=Trifluoromethyl,R²═R³═R⁴=H, R¹=Fluoro, R⁵═R⁶=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 402 (Structure 30 ofScheme V, where R=trifluoromethyl, R²═R³═R⁴=H, R¹=fluoro) and TFA inplace of Compound 200 and difluoroacetic acid. Compound 404 was isolatedas a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) 12.67 (s, 1H), 7.53 (dd,J=2.1, 7.2, 1H), 7.36 (d, J=9.2, 1H), 7.18 (d, J=2.1, 1H), 4.39 (q,J=8.8, 4H).

EXAMPLE 167 6-(bis-Isobutylamino)-4-methyl-2(1H)-quinolinone (Compound405, Structure 31 of Scheme V, Where R=Methyl, R¹═R²═R³═R⁴=H,R⁵═R⁶=Isobutyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 375 (Structure 30 ofScheme V, where R=methyl, R¹═R²═R³═R⁴=H) and isobutyric acid. Compound405 was isolated as a yellow solid: ¹H NMR (CDCl₃, 500 MHz) 10.00-10.20(bs, 1H), 7.12 (d, J=8.9, 1H), 6.98 (dd, J=2.4, 8.9, 1H), 6.78 (d,J=2.4, 1H), 6.52 (s, 1H), 3.17 (d, J=7.0, 4H), 2.44 (s, 3H), 2.07(sextet, J=7.0, 2H), 0.93 (d, J=6.7, 12H).

EXAMPLE 1683-Fluoro-6-(N-methyl-N-2,2,2-trifluorofluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 406, Structure 31 of Scheme V, Where R=Trifluoromethyl,R²═R³═R⁴=H, R¹=Fluoro, R⁵=2,2,2-Trifluoroethyl, R⁶=Methyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 403 (Structure 31 ofScheme V, where R=trifluoromethyl, R²═R³═R⁴═R⁶=H, R¹=fluoro,R⁵=2,2,2-trifluoroethyl) and parafomaldehyde in place of Compound 200and propionaldehyde. Compound 406 was isolated as a yellow solid: ¹H NMR(400 MHz, CDCl₃) 12.25 (bs, 1H), 7.41 (d, J=8.7, 1H), 7.14 (dd, J=2,2,8.8, 1H), 7.13 (d, J=2.1, 1H), 3.91 (q, J=8.8, 2H), 3.13 (s, 3H).

EXAMPLE 169 7-Bromo-6-isopropylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 407, Structure 31of Scheme V, Where R=Trifluoromethyl,R¹═R²═R⁴═R⁶=H, R³=Bromo, R⁵=Isopropyl)

6-Amino-7-bromo-4-trifluoromethyl-2(1H)-quinolinone (Compound 408,Structure 30 of Scheme V, where R=Trifluoromethyl, R¹═R²═R⁴=H,R³=bromo):

To a solution of Compound 200 (Structure 3 of Scheme V) in methylenechloride (0.1-0.5 M) was added NBS (1.1 equiv) and the reaction mixturewas stirred at room temperature for 30 min. The mixture was concentratedand chromatography afforded Compound 408 as a yellow solid.

7-Bromo-6-isopropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound407, Structure 31 of Scheme V, where R=trifluoromethyl, R¹═R²═R⁴═R⁶=H,R³=bromo, R⁵=isopropyl):

This compound was prepared in a similar fashion as that described inExample 3, General Procedure V but using Compound 408 in place ofCompound 200. Compound 407 was isolated as a yellow solid: ¹H NMR (400MHz, CDCl₃) 11.3 (bs, 1H), 7.56 (s, 1H), 7.07 (s, 1H), 6.89 (s, 1H),4.20 (d, J=5.8, 1H), 3.70-3.65 (m, 1H), 1.30 (d, J=6.3, 6H).

EXAMPLE 1706-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-hydroxy-2(1H)-quinolinone(Compound 409, Structure 31 of Scheme V, Where R=Hydroxy, R¹═R²═R³═R⁴=H,R⁵═R⁶=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from 6-amino-4-hydroxy-2(1H)-quinolinone(Compound 410, Structure 30 of Scheme V, where R=hydroxy, R¹═R²═R³═R⁴=H)and trifluororacetic acid. Compound 409 was isolated as a yellow solid.¹H NMR (CDCl₃, 500 MHz) 7.55 (d, J=2.9, 1H), 7.40 (dd, J=2.9, 9.3, 1H),7.31(d, J=9.3, 1H), 5.91(s, 1H), 4.23 (q, J=8.3, 4H).

EXAMPLE 1716-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-methoxy-2(1H)-quinolinone(Compound 411, Structure 31 of Scheme V, Where R=Methoxy, R¹═R²═R³═R⁴=H,R⁵═R⁶=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from 6-amino-4-methoxy-2(1H)-quinolinone(Compound 412, Structure 30 of Scheme V, where R=methoxy, R¹═R²═R⁴=H) H)and trifluororacetic acid. Compound 411was isolated as a yellow solid.¹H NMR (400 MHz, CDCl₃) 10.52 (bs, 1H), 7.44, (d, J=2.7, 1H), 7.29 (d,J=8.8, 1H), 7.18 (dd, J=8.8, 2.7, 1H), 6.01(s, 1H), 4.06 (q, J=8.53,4H), 3.99 (s, 3H).

EXAMPLE 1726-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-difluoromethyl-2(1H)-quinolinone(Compound 413, Structure 31 of Scheme V, Where R=Difluoromethyl,R¹═R²═R³═R⁴=H, R⁵═R⁶=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from6-amino-4-difluoromethyl-2(1H)-quinolinone (Compound 414, Structure 30of Scheme V, where R=difluoromethyl, R¹═R²═R³═R⁴=H) and trifluororaceticacid. Compound 413 was isolated as a yellow solid. ¹H NMR (CDCl₃, 500MHz) 7.47 (dd, J=2.9, 9.3, 1H), 7.45 (m, 1H), 7.39 (d, J=9.3, 1H), 7.15(t J=53.7, 1H), 6.86 (s, 1H), 4.26 (q, J=8.8, 4H).

EXAMPLE 173 6-(bis-N,N-2,2,2-Trifluoroethyl)amino-2(1H)-quinolinone(Compound 415, Structure 31 of Scheme V, Where R═R¹═R²═R³═R⁴=H,R⁵═R⁶=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from 6-amino-2(1H)-quinolinone (Compound416, Structure 30 of Scheme V, where R═R¹═R²═R³═R⁴=H) andtrifluororacetic acid. Compound 415 was isolated as a yellow solid. ¹HNMR (CDCl₃, 500 MHz) 7.92 (d, J=9.8, 1H), 7.40 (dd, J=2.9, 8.8, 1H),7.35 (d, J=2.9, 1H), 7.32 (d, J=8.8, 1H), 6.61 (d, J=9.8, 1H), 4.25 (q,J=8.8, 4H).

EXAMPLE 1744-Chloro-6-(bis-N,N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone(Compound 417, Structure 31 of Scheme V, Where R=Chloro, R¹═R²═R³═R⁴=H,R⁵═R⁶=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from 6-amino-4-chloro-2(1H)-quinolinone(Compound 418, Structure 30 of Scheme V, where R=chloro, R¹═R²═R³═R⁴=H)and trifluororacetic acid. Compound 417 was isolated as a yellow solid.¹H NMR (500 MHz, CDCl₃) 10.30 (bs, 1H), 7.47 (d, J=2.4, 1H), 7.32 (d,J=9.3, 1H), 7.25 (dd, J=9.3, 2.4, 1H), 6.89 (s, 1H), 4.10 (q, J=8.3,4H).

EXAMPLE 175 7-Methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 419,Structure 29 of Scheme V, Where R=Trifluoromethyl, R¹═R²═R⁴=H,R³=Methoxy)

In a 50-mL flask, a solution of meta-anisidine (5 mL, 44 mmol) and ethyl4,4,4-trifluoroacetoacetate (7.8 mL, 53 mmol, 1.2 equiv) in toluene (5mL) was heated to reflux for 16 h, cooled and the white precipitatefiltered off and washed with hexane (10 mL). The crude precipitate wasthen heated in EtOH (15 mL) with a catalytic amount of p-toluenesulfonicacid. After complete conversion, 4-6 h, the solvent was removed and thecrude reaction mixture was re-dissolved in EtOAc (200 mL) and washedwith water (2×20 mL), Brine (20 mL), dried (MgSO₄), filtered andconcentrated to give 4.0 g (37%) of Compound 419 as a white solid: ¹HNMR (400 MHz, DMSO-d₆) 12.18 (s, 1H), 7.62 (dd, J=8.4, 1.5, 1H), 6.95(dd, J=8.2, 2,2, 1H), 6.93 (s, 1H), 6.78 (s, 1H), 3.84 (s, 3H).

EXAMPLE 176 5,7-Dimethoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound420, Structure 29 of Scheme V, Where R=Trifluoromethyl, R¹═R⁴=H,R²═R³=Methoxy)

This compound was prepared in a similar fashion as that described inExample 175 but using 3,5-dimethoxyaniline in place of 3-anisidine.Compound 420 was isolated as a white solid: ¹H NMR (400 MHz, DMSO-d₆)12.11 (bs, 1H), 6.71(s, 1H), 6.56 (d, J=2.2, 1H), 6.46 (d, J=2.2, 1H),3.87 (s, 3H), 3.83 (s, 3H).

EXAMPLE 177(R)-6-(2-Hydroxymethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 421, Structure 33 of Scheme Va, Where n=1)

(R)-6-(2-Methoxycarbonyl-1-pyrrolidino)-4-trifluoromethyl-2-isopropyloxyquinoline(Compound 422, Structure 32 of Scheme VI, where R=methyl, n=1)

This compound was prepared in a similar fashion as that described inExample 101, General Procedures XIII and XIV from Compound 309(Structure 17 of Scheme III) and D-proline methyl ester.

(R)-6-(2-Hydroxymethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 421, Structure 33 of Scheme VI, where n=1)

This compound was prepared from Compound 422 by a metal hydridereduction and isolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz)1.00-11.20 (bs, 1H), 7.26-7.27 (m, 1H), 7.12 (dd, J=2.7, 9.5, 1H),7.06(s, 1H), 6.96 (s, 1H), 3.91-4.14 (m, 1H), 3.71(s, 2H), 3.58 (t,J=7.3, 1H), 3.19-3.24 (m, 1H), 2.05-2.16 (m, 5H).

EXAMPLE 178(R)-6-(2-Methoxymethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 423, Structure 34 of Scheme VI, Where R=Methoxymethyl, n=1)

This compound was prepared by methylation of Compound 421 and isolatedas yellow solid. ¹H NMR (CDCl₃, 500 MHz) 11.60-11.80 (bs, 1H), 7.32 (d,J=8.9, 1H), 7.08 (dd, J=2.4, 8.9, 1H), 7.07 (s, 1H), 6.96 (s, 1H),3.92-3.97 (m, 1H), 3.44-3.54 (m, 2H), 3.40 (s, 3H), 3.30 (dd, J=7.9,9.5, 1H), 3.16-3.21 (m, 1H), 2.01-2.13 (m, 4H).

EXAMPLE 179(±)-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 424, Structure 34 of Scheme VI, Where R=Chloromethyl, n=2)

This compound was prepared from Compound 331(Structure 33 of Scheme VI,where n=2) by tosylation and chloride displacement. Compound 424 wasisolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz) 11.60-11.70 (bs, 1H),7.35 (bs, 2H), 7.25 (s, 1H), 7.08 (s, 1H), 3.96-4.00 (m, 1H), 3.62 (t,J=10.7, 1H), 3.44-3.47 (m, 1H), 3.29-3.33 (m, 1H), 3.01-3.06 (m, 1H),2.08-2.18 (m, 1H), 1.82-1.91(m, 2H), 1.61-1.74 (m, 3H).

EXAMPLE 180(±)-6-(2-Cyanothiomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 425, Structure 34 of Scheme VI, Where R=CH₂SCN, n=2)

This compound was prepared from Compound 331(Structure 33 of Scheme VI,where n=2) by tosylation and thiocyanate displacement. Compound 425 wasisolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz) 12.00-12,20 (bs, 1H),7.39-7.42 (m, 2H), 7.29 (s, 1H), 7.10 (s, 1H), 4.02 (sextet, J=4.4, 1H),3.25-3.27 (m, 1H), 3.16 (dd, J=4.9, 12.7, 1H), 3.05-3.10 (m, 2H),1.96-2.05 (m, 2H), 1.68-1.80 (m, 4H).

EXAMPLE 181(±)-6-(2-Thiomethoxymethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 426, Structure 34 of Scheme VI, Where R=—CH₂SMe, n=2)

This compound was prepared from Compound 331(Structure 33 of Scheme VI,where n=2) by tosylation and methanethiol displacement. Compound 426 wasisolated as yellow oil. ¹H NMR (CDCl₃, 500 MHz) 11.80-12.00 (bs, 1H),7.32-7.36 (m, 2H), 7.23 (s, 1H), 7.08 (s, 1H), 3.92-3.95 (m, 1H),3.28-3.31(m, 1H), 3.00-3.05 (m, 1H), 2.72 (dd, J=9.8, 13.2, 1H), 2.45(dd, J=3.4, 13.2, 1H), 2.04-2.08 (m, 1H), 2.03 (s, 3H), 1.81-1.90 (m,2H), 1.60-1.70 (m, 3H).

EXAMPLE 182(±)-6-(2-Cyanomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 427, Structure 34 of Scheme VI, Where R=Cyanomethyl, n=2)

This compound was prepared from Compound 331 (Structure 33 of Scheme VI,where n=2) by tosylation and cyanide displacement. Compound 427 wasisolated as red solid. ¹H NMR (CDCl₃, 500 MHz) 12.20-12.40 (bs, 1H),7.51-7.54 (m, 4H), 4.11-4.15 (m, 1H), 3.25-3.29 (m, 1H), 3.00-3.04 (m,1H), 2.59 (dd, J=8.8, 17.1, 1H), 2.40 (dd, J=4.9, 17.1, 1H), 1.84-2.03(m, 2H), 1.60-1.80 (m, 4H).

EXAMPLE 183(±)-6-(2-Bromomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 428, Structure 34 of Scheme VI, Where R=Bromomethyl, n=2)

This compound was prepared from Compound 331 (Structure 33 of Scheme VI,where n=2) by tosylation and bromide displacement. Compound 428 wasisolated as red solid. ¹H NMR (CDCl₃, 500 MHz) 11.40-11.60 (bs, 1H),7.34-7.35 (m, 2H), 7.25 (s, 1H), 7.08 (s, 1H), 4.00-4.03 (m, 1H), 3.50(t, J=9.8, 1H), 3.27-3.34 (m, 2H), 3.02-3.06 (m, 1H), 2.15-2.18 (m, 1H),1.83-1.92 (m, 2H), 1.61-1.73 (m, 3H).

EXAMPLE 184(±)-6-(2-Iodomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 429, Structure 34 of Scheme VI, Where R=Iodomethyl, n=2)

This compound was prepared from Compound 331 (Structure 33 of Scheme VI,where n=2) by tosylation and iodide displacement. Compound 429 wasisolated as red solid. ¹H NMR (CDCl₃, 500 MHz) 11.80-12.00 (bs, 1H),7.38 (m, 2H), 7.29-7.26 (m, 1H), 7.08 (s, 1H), 3.80-4.00 (m, 1H),3.22-3.37 (m, 2H), 3.12-3.20 (m, 1H), 3.01-3.10 (m, 1H), 1.65-1.66 (m,2H). 1.24-1.30 (m, 4H).

EXAMPLE 185(+)R-6-(2-Iodomethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 430, Structure 34 of Scheme VI, Where R=Iodomethyl, n=1)

This compound was prepared in a similar fashion as that described inExamples 101 and 184 from Compound 309 (Structure 17 of Scheme III) andD-proline and isolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz) 12.5(bs, 1H), 7.41 (d, J=8.9, 1H), 7.09 (s, 1H), 6.96 (dd, J=8.9, 2.4, 1H),6.83 (s, 1H), 4.09-4.07 (m, 1H), 3.60-3.56 (m, 1H), 3.33-330 (m, 1H),3.27-3.24 (m, 1H), 3.01(t, J=10.4, 1H), 2.19-2.05 (m, 4H).

EXAMPLE 186(±)-6-(2-Fluoromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 431, Structure 34 of Scheme VI, Where R=Fluoromethyl, n=2)

This compound was prepared from Compound 331 (Structure 33 of Scheme VI,where n=2) by tosylation and fluoride displacement. Compound 431 wasisolated as red solid. ¹H NMR (CDCl₃, 500 MHz) 11.73 (bs, 1H), 7.32 (d,J=6.9, 1H), 7.21-7.19 (m, 1H), 7.06-7.04 (m, 2H), 4.95-4.82 (m, 1H),3.83-3.75 (m, 2H), 3.61-3.40 (m, 2H), 2.01-1.70 (m, 6H).

EXAMPLE 187(±)S-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 432, Structure 34 of Scheme VI, Where R=Chloromethyl, n=2) and(−)R-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 433, Structure 34 of Scheme VI, Where R=Chloromethyl, n=2)

These compounds were prepared from separation of Compound 424 by chiralHPLC and the absolute sterochemistry were established by independentsynthesis from optically active commercial material. Compound 432:[α]_(D)=+63; Compound 433: [α]_(D)=−63.

EXAMPLE 188(±)R-6-(2-Chloromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 434, Structure 34 of Scheme VI, Where R=Chloromethyl n=1) and(−)S-6-(2-Chloromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 435, Structure 34 of Scheme VI, Where R=Chloromethyl, n=1)

Compound 434 was prepared in a similar synthetic sequence as thatdescribed in Examples 101 and 179 from Compound 309 (Structure 17 ofScheme III) and D-proline. Compound 434was isolated as yellow solid. ¹HNMR (CDCl₃, 500 MHz) 11.90-12.10 (s, 1H), 7.37 (d, J=8.8, 1H), 7.08 (s,1H), 7.07 (s, 1H), 6.88 (s, 1H), 4.01-4.04 (m, 1H), 3.63 (dd, J=2.4,10.7, 1H), 3.54-3.57 (m, 1H), 3.31 (dd, J=9.8, 11.2, 1H), 3.22-3.27 (m,1H), 2.10-2.23 (m, 4H).

Compound 435 was prepared in the same fashion from Compound 309 andL-proline.

EXAMPLE 189R-6-(2-Difluoromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 436, Structure 34 of Scheme VI, Where R=Difluoromethyl, n=1)

Compound 436 was prepared in a similar synthetic sequence as thatdescribed in Examples 101 and 179 from Compound 309 (Structure 17 ofScheme III) and D-proline and isolated as yellow solid. ¹H NMR (CDCl₃,500 MHz) 11.80-12.00 (bs, 1H), 7.35(d, J=9.2, 1H), 7.13 (dd, J=2.4, 9.2,1H), 7.08 (s, 1H), 7.02 (s, 1H), 5.81 (dt, J=3.6, 56.1, 1H), 4.03-4.09(m, 1H), 3.66 (t, J=7.9, 1H), 3.26 (q, J=8.5, 1H), 2.04-2,28 (m, 4H).

EXAMPLE 190(±)-6-(2l-(1l-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 437, Structure 36 of Scheme VI, Where R=Trifluoromethyl, n=2)and(±)-6-(2l-(1u-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 438, Structure 36 of Scheme VI, Where R=Trifluoromethyl, n=2)

(±)-6-(2-Formyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 439, Structure 35 of Scheme VI, where R=formyl, n=2)

Compound 439 was prepared from Compound 331 (Structure 33 of Scheme VI,where n=2) by oxidation.

(±)-6-(2l-(1l-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 437, Structure 36 of Scheme VI, where R=trifluoromethyl, n=2)and(±)-6-(2l-(1u-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 438, Structure 36 of Scheme VI, where R=trifluoromethyl, n=2)

These compounds were prepared by the following General Procedure XVIIfrom Compound 439:

To the aldehyde (2.2 mmol) in THF (22 mL) at −78° C. was added thenucleophile or the TMSCF₃ (2.9 mmol, equiv). The reaction mixture waswarmed to rt and stirred for 5-24 h. Work up involved quenching with H₂Oand extraction with EA. The organic layers were dried over MgSO₄,filtered, and concentrated in vacuo. by flash chromatography(EtOAc:hexane mixtures) afforded the desired products as diastereomers.

Compound 437 was isolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz) 10.65(bs, 1H), 7.37-7.28 (m, 3H), 7.08 (s, 1H), 4.35-4.32 (m, 1H), 4.11-3.94(m, 1H), 3.65 (d, J=15.6, 1H), 3.47 (s, 1H), 3.21-3.16 (m, 1H),1.85-1.67 (m, 6H).

Compound 438 was isolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz) 11.50(bs, 1H), 7.37-7.35 (m, 3H), 7.08 (s, 1H), 4.19-4.10 (m, 1H),3.82-3.81(m, 1H), 3.25-3.22 (m, 2H), 2.48 (bs, 1H), 2.01-1.98 (m, 1H),1.86-1.85 (m, 2H), 1.72-1.70 (m, 2H), 1.61-1.57 (m, 1H).

EXAMPLE 191(±)-6-(2-Difluoromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 440, Structure 34 of Scheme VI, Where R=Difluoromethyl, n=2)

Compound 440 was prepared in a similar fashion as that described inExample 179 from Compound 439 (Structure 35 of Scheme VI, where n=2) andisolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz) 11.60-11.80 (bs, 1H),7.31-7.33 (m, 2H), 7.25 (s, 1H), 7.08(s, 1H), 5.90 (dt, J=4.3, 55.8,1H), 3.97-4.02 (m, 1H), 3.42 (d, J=11.9, 1H), 3.24 (t, J=10.7, 1H),2.04-2.06 (m, 1H). 1.85-1.89 (m, 2H), 1.69-1.72 (m, 3H).

EXAMPLE 192(±)-6-(2-Aminomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 441Structure 34 of Scheme VI, Where R=Aminomethyl, n=2)

Compound 441 was prepared in a similar fashion as that described inExample 179 from Compound 439 (Structure 35 of Scheme VI, where n=2) andisolated as yellow solid. ¹H NMR (500 MHz, CDCl₃) 7.37 (dd, J=9.0, 2.5,1H), 7.35 (d, J=9.0, 1H), 7.24 (m, 1H), 7.07 (s, 1H), 3.70 (m, 1H), 3.32(m, 1H), 3.12 (m, 1H), 2.92 (dd, J=12.8, 5.9, 1H), 2.79 (dd, J=12.8,6.5, 1H), 1.85-1.65 (m, 6H).

EXAMPLE 193(R)-6-(2-Vinyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 442, Structure 34 of Scheme VI, Where R=Vinyl, n=1)

Compound 442 was prepared in a similar fashion as that described inExample 179 from(R)-6-(2-Formyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 443, Structure 35 of Scheme VI, where n=1) and isolated asyellow oil. ¹H NMR (500 MHz, CDCl₃) 11.17 (s, 1H) 7.24 (d, J=8.9, 1H),7.04 (s, 1H), 6.98 (dd, J=8.9, 2.4, 1H), 6.90 (m, 1H), 5.81(ddd, J=16.2,10.4, 5.8, 1H), 5.15 (dd, J=10.4, 1.5, 1H), 5.14 (dd, J=16.2, 1.5, 1H),4.20 (m, 1H), 3.55 (td, J=8.2, 2.9, 1H), 3.33 (q, J=7.5, 1H), 2,21(m,1H), 2.06 (m, 2H), 1.91(m, 1H).

EXAMPLE 194(±)-6-(2-Vinyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 444, Structure 34 of Scheme VI, Where R=Vinyl, n=2)

Compound 444 was prepared in a similar fashion as that described inExample 179 from Compound 439 (Structure 35 of Scheme VI, where n=2) andisolated as yellow oil. ¹H NMR (500 MHz, CDCl₃) 11.20 (s, 1H), 7.31(dd,J=9.1, 2.5, 1H), 7.26 (d, J=9.1, 1H), 7.25 (m, 1H), 7.04 (s, 1H), 5.78(ddd, J=17.3, 10.7, 6.6, 1H), 5.08 (dd, J=10.7, 1.2, 1H), 5.05 (dd,J=17.3, 1.2, 1H), 4.15 (m, 1H), 3.24-3.17 (m, 2H), 2.05-1.63 (m, 6H).

EXAMPLE 195(±)-6-(2-Benzyloxyethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 445, Structure 34 of Scheme VI, Where R=Benzyloxyethyl, n=2)

Compound 445 was prepared by benzylation of Compound 343 (Structure 34of Scheme VI, where R=2-hydroxyethyl, n=2) and isolated as yellow oil.¹H NMR (500 MHz, CDCl₃) 11.40 (s, 1H), 7.36-7.22 (m, 7H), 7.18 (m, 1H),7.06 (s, 1H), 4.40 (d, J=11.9, 1H), 4.38 (d, J=11.9, 1H), 4.05 (m, 1H),3.43 (dd, J=9.2, 6.2, 1H), 3.40 (dd, J=9.2, 6.4, 1H), 3.33 (dd, J=11.9,2.4, 1H), 3.05 (m, 1H), 1.92-1.63 (m, 8H).

EXAMPLE 196(±)-6-(2-(2,2-Difluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 446, Structure 34 of Scheme VI, Where R=2,2-Difluoroethyl,n-=2)

Compound 446 was prepared from Compound ? (Structure ? of Scheme Va,where R=, n=2) and isolated as yellow solid. ¹H NMR (500 MHz, CDCl₃)10.95 (bs, 1H), 7.32 (dd, J=9.0, 2.5, 1H), 7.28 (d, J=9.0, 1H), 7.22 (m,1H), 7.07 (s, 1H), 5.78 (tt, J=56.4, 4.6, 1H), 4.08 (m, 1H), 3.34 (m,1H), 3.03 (m, 1H), 2.12-1.65 (m, 8H).

EXAMPLE 197(±)-6-(2-Trifluoroacetamidomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 447, Structure 34 of Scheme VI, WhereR=Trifluoroacetamidomethyl, n=2)

Compound 447 was prepared by acetylation of Compound 441(Structure 34 ofScheme VI, where R=aminomethyl, n=2) and isolated as yellow solid.R_(f)=0.32 (1:1CH₂Cl₂:MeOH).

EXAMPLE 198(±)-6-(2-(2-Ethoxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 448, Structure 34 of Scheme VI, Where R=2-Ethoxyethyl, n=2)

Compound 448 was prepared by ethylation of Compound 343 (Structure 34 ofScheme VI, where R=2-hydroxyethyl, n=2) and isolated as yellow solid. ¹HNMR (500 MHz, CDCl₃) 11.86 (bs, 1H), 7.36 (dd, J=9.3, 2.5 1H, 7.31 (d,J=9.3, 1H), 7.17 (bs, 1H), 7.07 (s, 1H), 4.02 (m, 1H), 3.40-3.31 (m,5H), 3.06 (m, 1H), 1.90-1.62 (m, 8H), 1.15 (t, J=7.0, 3H).

EXAMPLE 199(±)-6-(2-(4-Trifluoromethyl)benzyloxyethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 449, Structure 34 of Scheme VI, WhereR=4-Trifluoromethylbenzyloxyethyl, n=2)

Compound 449 was prepared by benzylation of Compound 343 (Structure 34of Scheme VI, where R=2-hydroxyethyl, n=2) and isolated as yellow solid.¹H NMR (CDCl₃, 500 MHz) 11.00-11.20 (bs, 1H), 7.58 (d, J=8.2, 2H), 7.38(d, J=7.9, 2H), 7.31-7.33 (m, 1H), 7.22 (d, J=8.2, 1H), 7.18 (bs, 1H),7.05 (s, 1H), 4.43 (s, 2H), 4.05-4.09 (m, 1H), 3.44 (q, J=6.7, 2H), 3.33(d, J=11.9, 1H), 3.05-3.08 (m, 1H), 1.63-1.96 (m, 8H).

EXAMPLE 200(+)-6-(2R-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)4-trifluoromethyl-2(1H)-quinolinone(Compound 450, Structure 36 of Scheme VI, Where R=trifluoromethyl, n=1)and(−)6-(2R-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)4-trifluoromethyl-2(1H)-quinolinone(Compound 451, Structure 36 of Scheme VI, Where R=Trifluoromethyl, n=1)

Compounds 450 and 451 were prepared in a similar synthetic sequence asthat described in Example 190 from Compound 309 (Structure 17 of SchemeIII) and D-proline. Compound 450 was isolated as yellow solid. ¹H NMR(CDCl₃, 500 MHz) 10.10 (bs, 1H), 7.16-7.07 (m, 2H), 7.03 (s, 1H), 6.99(s, 1H), 4.14 (d, J=6.8, 1H), 3.79 (d, J=6.8, 1H), 3.66-3.61 (m, 1H),3.21-3.18 (m, 2H), 2.19-2.04 (m, 4H). Compound 451 was also isolated asyellow solid. ¹H NMR (CDCl₃, 500 MHz) 11.05 (bs, 1H), 7.28 (d, J=8.9,1H), 7.04-7.01 (m, 2H), 6.89 (s, 1H), 4.40-4.39 (m, 1H), 4.14 (d, J=7.3,1H), 3.65 (dt, J=8.2, 3.7, 1H), 3.25 (q, J=7.9, 1H), 2.56 (s, 1H),2.47-2.44 (m, 1H), 2,28-2,23 (m, 1H), 2.15-2.01 (m, 2H).

EXAMPLE 2016-(2S-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 452, Structure 36 of Scheme VI, Where R=Trifluoromethyl, n=1)and6-(2S-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 453, Structure 36 of Scheme VI, Where R=Trifluoromethyl, n=1)

Compounds 452 and 453 were prepared in a similar synthetic sequence asthat described in Example 190 from Compound 309 (Structure 17 of SchemeIII) and L-proline. Compounds 452 and 453 were isolated as yellow solid.

EXAMPLE 202(±)-6-(2l-(1l-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 454, Structure 36 of Scheme VI, Where R=Methyl, n=2) and(±)-6-(2l-(1u-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 455, Structure 36 of Scheme VI, Where R=Methyl, n=2)

These compounds were prepared in a similar fashion as that described inExample 190, General Procedure XVII from Compound 439 and methyl anion.

Compound 454 was isolated as yellow oil. ¹H NMR (CDCl₃, 500 MHz)10.00-10.20 (bs, 1H), 7.36 (dd, J=2.4, 8.8, 1H), 7.32 (s, 1H), 7.20 (d,J=9.3, 1H), 7.06 (s, 1H), 4.25-4.30 (m, 1H), 3.59 (d, J=14.0, 1H),3.41-3.44 (m, 1H), 3.31-3.36 (m, 1H), 2.75 (bs, 1H), 1.60-1.75 (m, 6H),1.29 (d, J=5.9, 3H).

Compound 455 was isolated as yellow oil. ¹H NMR (CDCl₃, 500 MHz)10.50-10.60 (bs, 1H), 7.38-7.40 (m, 1H), 7.30 (d, J=9.3, 1H), 7.07 (s,1H), 3.95-3.98 (m, 1H), 3.23-3.25 (m, 1H), 3.11-3.25 (m, 2H), 1.84-1.94(m, 3H), 1.67-1.78 (m, 4H), 1.10 (d, J=6.3, 3H).

EXAMPLE 203(−)-6-(2S-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 456, Structure 36 of Scheme VI, Where R=trifluoromethyl, n=2)and(+)-6-(2R-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 457, Structure 36 of Scheme VI, Where R=trifluoromethyl, n=2)

Compounds 456 ([α]_(D)=−28) and 457 ([α]_(D)=+28) were prepared bychiral HPLC separation of Compound 438.

EXAMPLE 204(−)-6-(2S-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 459, Structure 36 of Scheme VI, Where R=Trifluoromethyl, n=2)and(+)-6-(2R-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 458, Structure 36 of Scheme VI, Where R=Trifluoromethyl, n=2)

Compounds 458 ([α]_(D)=+50) and 459 ([α]_(D)=−51) were prepared bychiral HPLC separation of Compound 437.

EXAMPLE 205(±)-6-2l-(1l-Acetyloxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 460, Structure 37 of Scheme VI, Where R¹=Acetyl, R=Methyl,n=2)

This compound was prepared by acetylation of Compound 454 (Structure 36of Scheme VI, where R=methyl, n=2) and isolated as yellow oil. ¹H NMR(CDCl₃, 500 MHz) 10.80-11.00 (bs, 1H), 7.38-7.31 (m, 1H), 7.23 (d,J=9.3, 1H), 7.12 (s, 1H), 7.05 (s, 1H), 5.49-5.55 (m, 1H), 3.83-3.87 (m,1H), 3.35 (d, J=13.2, 1H), 3.21-3.26 (m, 1H), 1.64-1.81 (m, 6H), 1.50(s, 3H), 1.22 (d, J=6.3, 3H).

EXAMPLE 206(±)-6-2l-(1u-Acetyloxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 461, Structure 37 of Scheme VI, where R¹=Acetyl, R=Methyl,n=2)

This compound was prepared by acetylation of Compound 455 (Structure 36of Scheme VI, where R=methyl, n=2) and isolated as yellow oil. ¹H NMR(CDCl₃, 500 MHz) 11.80-12.00 (bs, 1H), 7.32 (d, J=9.3, 1H), 7.26-7.28(m, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 5.37-5.40 (m, 1H), 3.75-3.76 (m,1H), 3.40-3.46 (m, 1H), 3.12-3.17 (m, 1H), 1.59-1.81 (m, 9H), 1.14 (d,J=6.3, 3H).

EXAMPLE 207(±)-6-2l-(1u-Methoxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 462, Structure 37 of Scheme VI, Where R¹=Methyl,R=Trifluoromethyl, n=2)

This compound was prepared by methylation of Compound 438 (Structure 36of Scheme VI, where R=trifluoromethyl, n=2) and isolated as yellowsolid. ¹H NMR (CDCl₃, 500 MHz) 12.00-12.40 (bs, 1H), 7.37-7.39 (m, 2H),7.27-7.29 (m, 1H), 7.13 (s, 1H), 3.99 (q, J=4.9, 1H), 3.76-3.80 (m, 1H),3.53 (s, 3H), 3.44 (dt, J=4.0, 13.4, 1H), 3.24-3.29 (m, 1H), 2.01-2.08(m, 1H), 1.61-1.86 (m, 5H).

EXAMPLE 208(±)-6-2l-(1l-Methoxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 463, Structure 37 of Scheme VI, Where R¹=Methyl,R=Trifluoromethyl, n=2)

This compound was prepared by methylation of Compound 437 (Structure 36of Scheme VI, where R=trifluoromethyl, n=2) and isolated as yellowsolid. ¹H NMR (CDCl₃, 500 MHz) 12.00-12.40 (bs, 1H), 7.34-7.39 (m, 2H),7.20 (s, 1H), 7.10-7.15 (bs, 1H), 4.14-4.17 (m, 1H), 3.89-3.94 (m, 1H),3.57 (d, J=13.4, 1H), 3.35 (s, 3H), 3.19 (dt, J=3.0, 13.4, 1H),1.61-1.89 (m, 6H).

EXAMPLE 2097-Methoxy-6-(N-methyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 464, Structure 41 of Scheme VII, Where R=Methyl)

2-Methoxy-N-2,2,2-trifluoroethyl-4-nitroaniline (Compound 465):

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using 2-amino-5-nitroanisole andtrifluoroacetaldehyde hydrate in place of Compound 200 andpropionaldehyde. Compound 465 was isolated as a light brown crystallinesolid after recrystallization (1:1 EtOAc:hexanes, 30 mL): R_(f) 0.52(2:1 hexanes:EtOAc); ¹H NMR (400 MHz, acetone-d₆) 7.87 (dd, J=8.9, 2.4,1H), 7.69 (d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 6.38 (broad s, 1H), 4.20(qd, J=9.3, 7.1, 2H), 4.00 (s, 3H).

4-Amino-2-methoxy-N-2,2,2-trifluoroethylaniline (Compound 466, Structure39 of Scheme VII):

This compound was prepared by General Procedure III in Example 1 fromCompound 465 (8.40 g, 33.6 mmol), zinc dust (9.66 g, 0.148 mmol), andcalcium chloride dihydrate (10.9 g, 73.9 mmol) in 300 mL 95% EtOH/water.Compound 466 was isolated in 90% (6.7 g) yield as a deep purple oil:R_(f) 0.25 (1:1 hexanes:EtOAc); ¹H NMR (400 MHz, CDCl₃) 6.54 (d, J=8.1,1H), 6.20-6.30 (m, 2H), 4.15 (broad s, 1H), 3.81 (s, 3H), 3.68 (qd,J=9.0, 7.4, 2H), 3.38 (broad s, 2H).

7-Methoxy-6-(N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 467, Structure 40 of Scheme VII):

This compound was prepared according to General Procedure I in Example 1from Compound 466 (5.72 g, 26.0 mmol) and 4,4,4 trifluoroacetoacetate(4.56 mL, 5.74 g, 31.2 mmol) in 87 mL toluene, followed by treatmentwith 65 mL concentrated H₂SO₄. Compound 467 was isolated as a fluffyyellow solid: R_(f) 0.19 (4:1 EtOAc:CH₂Cl₂); ¹H NMR (400 MHz,acetone-d₆) 10.87 (broad s, 1H), 7.04 (s, 1H), 6.99 (broad s, 1H), 6.73(s, 1H), 5.54 (broad m, 1H), 4.07 (app quint, J=8.4, 2H), 3.98 (s, 3H).

7-Methoxy-6-(N-methyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 464, Structure 41 of Scheme VII, Where R=Methyl):

A solution of Compound 467 (24 mg, 0.070 mmol) and paraformaldehyde (21mg, 0.70 mmol) in 1.4 mL acetic acid was stirred for 15 min, whereuponNaBH₃CN (22 mg, 0.35 mmol) was added. After 18 h, the mixture waspartitioned between EtOAc (40 mL) and sat'd NaHCO₃ (40 mL). The organiclayer was washed with brine (20 mL), dried over MgSO₄, filtered andconcentrated. Flash chromatography (4:1 EtOAc:CH₂Cl₂) afforded 20 mg(81%) of Compound 464 as a yellow solid: R_(f) 0.38 (4:1 EtOAc:CH₂Cl₂);¹H NMR (400 MHz, CDCl₃) 12.9 (broad s, 1H), 7.37 (broad s, 1H), 6.96 (s,1H), 6.89 (s, 1H), 4.04 (s, 3H), 3.83 (q, J=9.3, 2H), 3.06 (s, 3H).

EXAMPLE 2107-Methoxy-6-(N-ethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 468, Structure 41 of Scheme VII, Where R=Ethyl)

A solution of Compound 467 (Structure 40 of Scheme VII) (10 mg, 0.030mmol) and acetaldehyde (13 mg, 0.30 mmol) in 1 mL acetic acid wasstirred for 20 min, whereupon NaBH₃CN (9.4 mg, 0.15 mmol) was added.After 18 h, the mixture was partitioned between EtOAc (30 mL) and sat'dNaHCO₃ (30 mL). The organic layer was washed with brine (20 mL), driedover MgSO₄, filtered and concentrated. Flash chromatography (3:2EtOAc:CH₂Cl₂) afforded 4.5 mg (41%) of Compound 468 as a yellow solid:R_(f) 0.40 (3:2 EtOAc:CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) 12.7 (broad s,1H), 7.45 (broad s, 1H), 6.95 (s, 1H), 6.88 (s, 1H), 4.02 (s, 3H), 3.76(q, J=9.4, 2H), 3.33 (q, J=7.1, 2H), 1.08 (t, J=7.0, 3H).

EXAMPLE 2117-Hydroxy-6-(2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 469, Structure 42 of Scheme VI, Where R=H)

A suspension of Compound 467 (Structure 40 of Scheme VII) (34 mg, 0.10mmol), NaH (60% mineral oil suspension, 16 mg, 0.40 mmol) and thiophenol(48 mg, 0.44 mmol) in 1.5 mL DMF was heated at 80° C. for 7 h. Themixture was poured into cold sat'd NH₄Cl (30 mL), and the aqueous layerwas extracted with EtOAc (2×30 mL). The combined organic layers werewashed with brine (20 mL), dried over MgSO₄, filtered, and concentrated.Flash chromatography (9:1 CH₂Cl₂:MeOH) afforded 13 mg (39%) of Compound469 as a yellow solid: R_(f) 0.17 (9:1 CH₂Cl₂:MeOH); ¹H NMR (400 MHz,acetone-d₆) 10.9 (broad s, 1H), 9.8 (v broad s, 1H), 7.00 (s, 2H), 6.68(s, 1H), 5.38-5.48 (m, 1H), 4.02-4.12 (m, 2H).

EXAMPLE 2126-(N-Cyclopropylmethyl-N-2,2,2-trifluoroethyl)amino-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 470, Structure 41 of Scheme VII, Where R=Cyclopropylmethyl)

This compound was prepared according to General Procedure IV in Example2 from Compound 467 (Structure 40 of Scheme VII) (33 mg, 0.097 mmol),cyclopropanecarboxaldehyde (34 mg, 0.48 mmol) and NaBH₃CN (37 mg, 0.59mmol) in 1 mL trifluoroacetic acid to afford 38 mg (96%) of Compound 470as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 11.0 (broad s, 1H), 7.46(broad s, 1H), 6.86 (s, 1H), 6.74 (s, 1H), 3.88 (s, 3H), 3.84 (q, J=9.3,2H), 3.08 (d, J=6.6, 2H), 0.80-0.90 (m, 1H), 0.40-0.50 (m, 2H),0.07-0.13 (m, 2H).

EXAMPLE 2136-(N-Cyclopropylmethyl-N-2,2,2-trifluoroethyl)amino-7-hydroxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 471, Structure 42 of Scheme VII, Where R=Cyclopropylmethyl)

A suspension of Compound 470 (35 mg, 0.089 mmol), NaH (60% mineral oilsuspension, 28 mg, 0.71 mmol) and thiophenol (83 mg, 0.76 mmol) in 1.3mL DMF was heated at 105° C. for 4 h. The mixture was poured into coldwater (20 mL) and neutralized with 2N NaHSO₄. The aqueous layer wasextracted with EtOAc (2×20 mL), and the combined organic layers werewashed with water (20 mL), brine (10 mL), dried over MgSO₄, filtered,and concentrated. Flash chromatography (7:3 EtOAc:CH₂Cl₂) afforded 14 mg(42%) of Compound 471 as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 12.3(broad s, 1H), 7.60 (broad s, 2H), 7.03 (s, 1H), 6.93 (s, 1H), 3.64 (q,J=8.9, 2H), 2.94 (d, J=6.9, 2H), 0.75-0.85 (m, 1H), 0.42-0.52 (m, 2H),0.05 (m, 2H).

EXAMPLE 2146-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 472, Structure 41 of Scheme VII, Where R=Isobutyl)

This compound was prepared according to General Procedure IV in Example2 from Compound 467 (Structure 40 of Scheme VII) (34 mg, 0.10 mmol),isobutyraldehyde (36 mg, 0.50 mmol) and NaBH₃CN (38 mg, 0.60 mmol) in 1mL trifluoroacetic acid to afford 24 mg (61%) of Compound 472 as ayellow solid: ¹H NMR (400 MHz, CDCl₃) 12.0 (broad s, 1H), 7.47 (broad s,1H), 6.93 (s, 1H), 6.82 (s, 1H), 4.00 (s, 3H), 3.73 (q, J=9.3, 2H), 3.04(d, J=7.2, 2H), 1.60-1.70 (m, 1H), 0.88 (t, J=6.6, 6H).

EXAMPLE 2156-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-7-hydroxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 473, Structure 42 of Scheme VII, Where R=Isobutyl)

A suspension of Compound 472 (Structure 41 of Scheme VII, whereR=isobutyl) (19 mg, 0.048 mmol), NaH (60% mineral oil suspension, 15 mg,0.38 mmol) and thiophenol (45 mg, 0.41 mmol) in 1.5 mL DMF was heated at105° C. for 4 h. The mixture was poured into cold water (20 mL) andneutralized with 2N NaHSO₄. The aqueous layer was extracted with EtOAc(2×20 mL), and the combined organic layers were washed with water (20mL), brine (10 mL), dried over MgSO₄, filtered, and concentrated. Flashchromatography (7:3 EtOAc:CH₂Cl₂) afforded 8.5 mg (46%) of Compound 473as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 12.1 (broad s, 1H), 7.60 (s,1H), 7.43 (broad s, 1H), 7.02 (s, 1H), 6.92 (s, 1H), 3.53 (q, J=8.9,2H), 2.93 (d, J=7.0, 2H), 1.55-1.65 (m, 1H), 0.93 (d, J=6.6, 6H).

EXAMPLE 2166-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-trifluoromethylcoumarin(Compound 474, Structure 45 of Scheme VIII, WhereR⁵═R⁶=2,2,2-Trifluoroethyl)

6-Amino-4-trifluoromethylcoumarin (Compound 475, Structure 44 of SchemeVIII):

This compound was prepared in a similar fashion as that described inExample 1, General Procedures I, II and III but using phenol in place ofaniline. Compound 475 was isolated as a yellow solid: ¹H NMR (500 MHz,CDCl₃) 7.21 (d, J=8.8, 1H), 7.10 (dd, J=8.8, 2.4, 1H), 7.00 (s, 1H),6.81 (s, 1H), 5.09 (bs, 2H).

6-(bis-2,2,2-Trifluoroethyl)amino-4-trifluoromethylcoumarin (Compound474, Structure of Scheme VIII, Where R⁵═R⁶=2,2,2-Trifluoroethyl):

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 475 and TFA in placeof Compound 200 and difluoroacetic acid. Compound 474 was isolated as ayellow solid: ¹H NMR (500 MHz, CDCl₃) 7.37 (d, J=9.3, 1H), 7.23 (dd,J=9.3, 2.9, 1H), 7.20 (s, 1H), 6.83 (s, 1H), 4.07 (q, J_(H-F)=8.3, 4H).

EXAMPLE 217(±)-3,4-Dihydro-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethylcoumarin(Compound 476, Structure 46 of Scheme VIII, WhereR⁵═R⁶=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compound 474(Structure 45 of Scheme VIII, where R⁵═R⁶=2,2,2-trifluoroethyl).Compound 476 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)7.07 (d, J=8.8, 1H), 6.98 (dd, J=8.8, 2.9, 1H), 6.82 (d, J=2.9, 1H),4.07-3.97 (m, 4H), 3.67-3.64 (m, 1H), 3.15 (dd, J=17.1, 1.9, 1H), 2.95(dd, J=17.1, 7.3, 1H).

EXAMPLE 218 6-(N-2,2,2-Trifluoroethyl)amino-4-trifluoromethylcoumarin(Compound 477, Structure 45 of Scheme VIII, Where R⁵=H,R⁶=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 475 (Structure 44 ofScheme VIII) and trifluoroacetyraldehyde. Compound 477 was isolated as ayellow solid: ¹H NMR (500 MHz, CDCl₃) 7.29 (d, J=8.8, 1H), 6.99 (dd,J=8.8, 2.9, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 4.15 (t, J=6.3, 1H),3.84-3.78 (m, 2H).

EXAMPLE 2196-(N-Isopropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethylcoumarin(Compound 478, Structure 45 of Scheme VIII, Where R⁵=isopropyl,R⁶=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV from Compound 475 (Structure 44 ofScheme VIII) by using acetone and trifluoroacetyraldehyde sequentially.Compound 478 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)7.33 (d, J=9.3, 1H), 7.24 (dd, J=9.3, 2.9, 1H), 7.18 (s, 1H), 6.79 (s,1H); 4.01-3.96 (m, 1H), 3.80 (q, J_(H-F)=8.8, 2H), 1.24 (d, J=6.8, 6H).

EXAMPLE 220 6-N-Isobutylamino-4-trifluoromethylcoumarin (Compound 479,Structure 45 of Scheme VIII, Where R⁵=Isobutyl, R⁶=H)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV from Compound 475 (Structure 44 ofScheme VIII) and isobutyraldehyde. Compound 479 was isolated as a yellowsolid: ¹H NMR (500 MHz, CDCl₃) 7.22 (d, J=8.8, 1H), 6.88 (dd, J=8.8,2.4, 1H), 6.75 (s, 2H), 3.89 (bs, 1H), 2.95 (d, J=6.4, 2H), 1.94-1.88(m, 1H), 1.02 (d, J=6.8, 6H).

EXAMPLE 221 6-N,N-Diethylamino-4-trifluoromethylcoumarin (Compound 480,Structure 45 of Scheme VIII, Where R⁵═R⁶=methyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV from Compound 475 (Structure 44 ofScheme VIII) and acetaldehyde. Compound 480 was isolated as a yellowsolid: ¹H NMR (500 MHz, CDCl₃) 7.27 (d, J=9.3, 1H), 6.99 (dd, J=9.3,2.9, 1H), 6.82 (s, 1H), 6.76 (s, 1H), 3.89 (q, J=7.3, 4H), 1.19 (t,J=7.3, 6H).

EXAMPLE 222 6-N,N-Dipropylamino-4-trifluoromethylcoumarin (Compound 481,Structure 45 of Scheme VIII, Where R⁵═R⁶=Propyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV from Compound 475 (Structure 44 ofScheme VIII) and propionaldehyde. Compound 481 was isolated as a yellowsolid: ¹H NMR (500 MHz, CDCl₃) 7.25 (d, J=9.3, 1H), 6.94 (dd, J=9.3,2.9, 1H), 6.77 (s, 1H), 6.75 (s, 1H), 3.27 (t, J=7.3, 4H), 1.65-1.57 (m,4H), 0.95 (t, J=7.3, 6H).

EXAMPLE 223 6-N-Propylamino-4-trifluoromethylcoumarin (Compound 482,Structure 45 of Scheme VIII, Where R⁵=H, R⁶=Propyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV from Compound 475 (Structure 44 ofScheme VIII) and propionaldehyde. Compound 482 was isolated as a yellowsolid: ¹H NMR (500 MHz, CDCl₃) 7.23 (d, J=8.8, 1H), 1.5 6.89 (dd, J=8.8,2.4, 1H), 6.77 (s, 1H), 6.76 (s, 1H), 3.82 (bs, 1H), 3.10 (t, J=7.3,2H), 1.71-1.64 (m, 2H), 1.03 (t, J=7.3, 3H).

EXAMPLE 224 6-(N-Isobutyl-N-propylamino)-4-trifluoromethylcoumarin(Compound 483, Structure 45 of Scheme VIII, Where R⁵=Isobutyl,R⁶=Propyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV from Compound 475 (Structure 44 ofScheme VIII) by using propionaldehyde and isobutyraldehyde. Compound 483was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 7.25 (d, J=9.3,1H), 6.95 (dd, J=9.3, 2.9, 1H), 6.78 (s, 1H), 6.75 (s, 1H), 3.30 (t,J=7.8, 2 H), 3.11 (d, J=7.3, 2H), 2.05-1.99 (m, 1H), 1.63-1.57 (m, 2H),0.95-0.93 (m, 9H).

EXAMPLE 2256-(N-2,2,2-Trifluoroethyl-N-propylamino)-4-trifluoromethylcoumarin(Compound 484, Structure 45 of Scheme VIII, WhereR⁵=2,2,2-Trifluoroethyl, R⁶=Propyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV from Compound 475 (Structure 44 ofScheme VIII) by using propionaldehyde and trifluoroacetaldehyde.Compound 484 was isolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃)7.31 (d, J=9.3, 1H), 7.08 (dd, J=9.3, 2.9, 1H), 6.98 (s, 1H), 6.79 (s,1H), 3.89 (q, J_(H-F)=8.8, 2H), 3.47 (t, J=7.8, 2H), 1.68-1.63 (m, 2H),0.96 (t, J=7.3, 3H).

EXAMPLE 2261,4-Dihydro-4,4-dimethyl-6-methylamino-1,3-benzo[d]oxazin-2-one(Compound 485, Structure 52 of Scheme IX, Where R¹═R²═R⁴=Methyl, R⁵=H,W=Oxygen)

1,4-Dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 486,Structure 49 of Scheme IX, Where R¹═R²=Methyl, W=Oxygen):

To a solution of 2-isopropenyl aniline (Structure 47 of Scheme IX, whereR¹=methyl) (1 mL, 7.3 mmol) and dry methylene chloride (20 mL) wasslowly added methylchloroformate (0.62 mL, 8.1 mmol). To this solutionwas added DMAP (0.9 g, 8.1 mmol) in methylene chloride (5 mL). Stirredat room temperature for 15 hrs. Partitioned reaction mixture betweenEtOAc (20 mL) and H₂O (5 mL). Washed organic layer with brine (3×10 mL),dried (Na₂SO₄) and concentrated in vacuo to afford crude as a colorlessoil. Purified by silica flash chromatography (10% Hex/EtOAc) to afford1.3 g of 2-isopropenyl-N-methylcarbamate aniline in 94% yield as acolorless oil. This product was dissolved in dichloroethane (20 mL) andtreated with p-TsOH (1.4 g) then heated to reflux. After 2 hrs. thereaction mixture was quenched with saturated NaHCO₃ and extracted withEtOAc (20 mL). The organic layer was washed with brine (3×10 mL), dried(Na₂SO₄), and concentrated in vacuo. Purified by silica flashchromatography (50% Hex/EtOAc) to afford 1.1 g of Compound 486 in 92%yield as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.70 (br s, 1H), 7.22(t, J=7.9, 1H), 7.13. (d, J=7.9, 1H), 7.05 (t, J=7.9, 1H), 6.86 (d,J=7.9, 1H), 1.71 (s, 6H).

6-Amino-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 487,Structure 51 of Scheme IX, Where R¹═R²=Methyl, W=Oxygen):

To a solution of Compound 486 (50 mg, 0.28 mmol) and conc. H₂SO₄ (2 mL),chilled to 0° C., was added fuming HNO₃ (0.03 mL). After 15 min. pouredreaction mixture onto ice and extracted with EtOAc (5 mL), washed withH₂O (5×1 mL) and brine (5×1 mL) then dried (Na₂SO₄) and concentrated invacuo to afford the crude product as a yellow solid. Dissolved in 2:1EtOAc/MeOH (5 mL) and hydrogenated over 10% Pd/C (10 mg) at rt and 1atm. After 15 hrs. filtered through plug of silica gel to afford 50 mgof Compound 487 in 90% yield as a white solid: ¹H NMR (400 MHz,acetone-d₆) 9.00 (br s, 1H), 6.93 (d, J=8.0, 1H), 6.60 (m, 2H), 1.64 (s,6H).

1,4-Dihydro-4,4-dimethyl-6-methylamino-1,3-benzo[d]oxazin-2-one(Compound 485, Structure 52 of Scheme IX, Where R¹═R²═R⁴=Methyl, R⁵=H,W=Oxygen):

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 487 andparaformaldehyde in place of Compound 200 and propionaldehyde. Compound485 was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 7.82 (bs,1H), 6.66 (d, J=8.5, 1H), 6.52 (d4, J=8.5, 2.1, 1H), 6.39 (d, J=2.1,1H), 2.83 (s, 3H), 1.69 (s, 6H).

EXAMPLE 2271,4-Dihydro-4,4-dimethyl-6-dimethylamino-1,3-benzo[d]oxazin-2-one(Compound 488, Structure 52 of Scheme IX, Where R¹═R²═R⁴═R⁵=Methyl,W=Oxygen)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII from Compound 487 (Structure 51 ofScheme IX, where R¹═R²=methyl, W=oxygen) (15 mg, 0.08 mmol) andparaformaldehyde (30 mg) to afford 5 mg (28%) of Compound 488 as a whitesolid: ¹H NMR (400 MHz, CDCl₃) 7.66 (br s, 1H), 6.69 (d, J=8.6, 1H),6.65 (dd, J=2.5, 8.6, 1H), 6.50 (d, J=2.5, 1H), 2.92 (s, 6H), 1.71 (s,6H).

EXAMPLE 2281,4-Dihydro-4,4-dimethyl-6-dipropylamino-1,3-benzo[d]oxazin-2-one(Compound 489, Structure 52 of Scheme IX, Where R¹═R²=Methyl,R⁴═R⁵=Propyl, W=Oxygen)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using Compound 487 (Structure 51of Scheme IX, where R¹═R²=H, W=oxygen) and propionaldehyde in place ofCompound 200 and paraformaldehyde. Compound 489 was isolated as a whitesolid: ¹H NMR (400 MHz, CDCl₃) 7.52 (br s, 1H), 6.64 (d, J=8.5, 1H),6.53 (dd, J=2.5, 8.5, 1H), 6.39 (d, J=2.5, 1H), 3.19 (t, J=7.5, 1H),1.55 (m, 10H), 0.92 (t, J=7.5, 1H).

EXAMPLE 2291,4-Dihydro-4,4-dimethyl-6-(bis-N,N-2,2,2-trifluoroethyl)amino-1,3-benzo[d]oxazin-2-one(Compound 490, Structure 52 of Scheme IX, Where R¹═R²=Methyl,R⁴═R⁵=2,2,2-Trifluoroethyl, W=Oxygen)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using Compound 487 (Structure 51of Scheme IX, where R¹═R²=H, W=oxygen) and trifluoroacetaldehyde inplace of Compound 200 and paraformaldehyde. Compound 490 was isolated asan orange oil: ¹H NMR (400 MHz, CDCl₃) 8.05 (brs, 1H), 6.85 (dd, J=2.6,8.7, 1H), 6.75 (d, J=8.7, 1H), 6.71 (d, J=2.6, 1H), 3.95 (q, J=8.6, 4H),1.70 (s, 6H).

EXAMPLE 2301,4-Dihydro-4,4-dimethyl-6-(N-2,2,2-trifluoroethyl)amino-1,3-benzo[d]oxazin-2-one(Compound 491, Structure 52 of Scheme IX, Where R¹═R²=Methyl,R⁴=2,2,2-Trifluoroethyl, R⁵=H, W=Oxygen)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 487 (Structure 51 ofScheme IX, where R¹═R²=H, W=oxygen) and trifluoroacetaldehyde in placeof Compound 200 and propionaldehyde. Compound 491 was isolated as awhite solid; ¹H NMR (400 MHz, CDCl₃) 8.16 (brs, 1H), 6.70 (d, J=8.5,1H), 6.59 (dd, J=2.6, 8.5, 1H), 6.47 (d, J=2.6, 1H), 3.80 (brs, 1H),3.73 (q, J=8.9, 2H), 1.69 (s, 6H).

EXAMPLE 231(±)-1,4-Dihydro-4-methyl-6-diallylamino-1,3-benzo[d]oxazin-2-one(Compound 492, Structure 52 of Scheme IX, Where R¹=Methyl, R²=H,R⁴═R⁵=Allyl, W=Oxygen)

(±)-1,4-Dihydro-4-methyl-1,3-benzo[d]oxazin-2-one (Compound 493,Structure 49 of Scheme IX, Where R¹=Methyl, R=H, W=Oxygen):

To a solution of 2-N-(tert-butoxycarbonyl)amino-(2-hydroxyethyl)benzene(0.58 g, 2.4 mmol) and dichloroethane (10 mL) was added TsOH (0.5 g, 2.6mmol) and the reaction mixture was heated to reflux. After 20 minutesthe reaction was quenched with saturated NaHCO₃ (10 mL) and extractedwith EtOAc (20 mL). The organic layer was washed with brine (3×5 mL),dried (Na₂SO₄), and concentrated in vacuo. The crude product waspurified by flash chromatography (50% EtOAc/hex) to afford 0.3 g (75%)of Compound 493 as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.64 (br s,1H), 7.27 (t, J=7.8, 1H), 7.08 (d overlapping t, 2H), 6.86 (d, J=7.8,1H), 5.50(q, J=6.7, 1H), 1.71 (d, J=6.7, 3H).

(±)-6-Amino-1,4-dihydro-4-methyl-1,3-benzo[d]oxazin-2-one (Compound 494,Structure 51 of Scheme IX, Where R¹=Methyl, R²=H, W=Oxygen):

To a solution of Compound 493 (130 mg, 0.8 mmol) and conc. H₂SO₄ (3 mL),chilled to 0° C., was added fuming HNO₃ (0.06 mL). After 15 min. pouredreaction mixture onto ice and extracted with EtOAc (5 mL), washed withH₂O (5×1 mL) and brine (5×1 mL) then dried (Na₂SO₄) and concentrated invacuo to afford the crude product as a yellow solid. Dissolved in 2:1EtOAc/MeOH (5 mL) and hydrogenated over 10% Pd/C (10 mg) at rt and 1atm. After 15 hrs. filtered through plug of silica gel and purified byPTLC (20×20 cm, 1000 μm, 50% EtOAc/hex) to afford 100 mg of Compound 494(70%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 8.47 (br s, 1H), 6.66(d, J=8.3, 1H), 6.59 (dd, J=2.2, 8.3, 1H), 6.43 (d, J=2.2, 1H), 5.40 (q,J=6.6, 1H), 3.63 (br s, 2H), 1.67 (d, J=6.6, 1H).

1,4-Dihydro-4-methyl-6-diallylamino-1,3-benzo[d]oxazin-2-one (Compound492, Structure 52 of Scheme IX, Where R¹=Methyl, R²=H, R⁴═R⁵=Allyl,W=Oxygen)

This compound was prepared in a similar fashion as that described inExample 77, General Procedure IX but using Compound 494 in place ofCompound 200. Compound 492 was isolated as a yellow oil: ¹H NMR (400MHz, CDCl₃) 6.66 (d, J=8.6, 1H), 6.60 (dd, J=2.5, 8.6, 1H), 6.42 (d,J=2.5, 1H), 5.82 (m, 2H), 5.43 (q, J=6.7, 1H), 5.16 (m, 4H), 3.88 (m,4H), 1.65 (d, J=6.7, 3H).

EXAMPLE 232 6-Amino-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound495, Structure 51 of Scheme IX, Where R¹═R²=Methyl, W=Carbon)

To a solution of 3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound496, Structure 49 of Scheme IX, where R¹═R²=methyl, W=carbon) (0.50 g,2.8 mmol) and conc. H₂SO₄ (10 mL), chilled to 0° C., was added fumingHNO₃ (0.12 mL). After 15 min. poured reaction mixture onto ice andextracted with EtOAc (20 mL), washed with H₂O (5×5 mL) and brine (5×5mL) then dried (Na₂SO₄) and concentrated in vacuo to afford the crudeproduct as a yellow solid. Dissolved in 9:1 EtOAc/MeOH (20 mL) andhydrogenated over 10% Pd/C (50 mg) at room temperature and 1 atm. After15 hrs. filtered through plug of silica gel to afford Compound 495 (0.48g) in 89% yield as an orange solid: ¹H NMR (400 MHz, CDCl₃) 7.67 (br s,1H), 6.66 (d, J=2.3, 1H), 6.57 (d, J=8.3, 1H), 6.51 (dd, J=2.3, 8.3,1H), 3.57 (br s, 2H), 2.43 (s, 2H), 1.28 (s, 6H).

EXAMPLE 233 6-Diallylamino-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone(Compound 497, Structure 52 of Scheme IX, Where R¹═R²=Methyl,R⁴═R⁵=Allyl, W=Carbon)

This compound was prepared in a similar fashion as that described inExample 77, General Procedure IX but using Compound 495 (Structure 51 ofScheme IX, where R¹═R²=methyl, W=carbon) in place of Compound 200.Compound 497 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.40(br s, 1H), 6.66 (d, J=2.7, 1H), 6.59 (d, J=8.0, 1H), 6.52 (dd, J=2.7,8.0, 1H), 5.90 to 5.81 (m, 2H), 5.21 to 5.16 (m, 4H), 3.89 (d, J=5.0,4H), 2.43 (s, 2H), 1.29 (s, 6H).

EXAMPLE 234 3,4-Dihydro-4,4-dimethyl-6-dipropylamino-2(1H)-quinolinone(Compound 498, Structure 52 of Scheme IX, Where R¹═R²=Methyl,R⁴═R⁵=Propyl, W=Carbon)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using Compound 495 (Structure 51of Scheme IX, where R¹═R²=methyl, W=carbon) and propionaldehyde in placeof Compound 200 and paraformaldehyde. Compound 498 was isolated as awhite solid: ¹H NMR (400 MHz, CDCl₃) 7.77 (br s, 1H), 6.62 (d, J=8.6,1H), 6.60 (d, J=2.7, 1H), 6.46 (dd, J=2.7, 8.5, 1H), 3.20 (t, J=7.5,4H), 2.44 (s, 2H), 1.60 (q, J=7.4, 4H), 1.31 (s, 6H), 0.93 (t, J=7.4,6H).

EXAMPLE 235 3,4-Dihydro-4,4-dimethyl-6-propylamino-2(1H)-quinolinone(Compound 499, Structure 52 of Scheme IX, Where R¹═R²=Methyl, R⁴=Propyl,R⁵=H, W=Carbon)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 495 (Structure 51 ofScheme IX, where R¹═R²=methyl, W=carbon) in place of Compound 200.Compound 499 was isolated as a colorless oil: ¹H NMR (400 MHz, CDCl₃)7.83 (br s, 1H), 6.59 (d, J=8.4, 1H), 6.54 (d, J=2.4, 1H), 6.41 (dd,J=2.4, 8.4, 1H), 3.56 (br s, 1H), 3.04 (t, J=7.1, 2H), 2.47 (s, 2H),1.61 (q, J=7.4, 4H), 1.27 (s, 6H), 0.97 (t, J=7.4, 6H).

EXAMPLE 2363,4-Dihydro-4,4-dimethyl-6-(N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone(Compound 500, Structure 52 of Scheme IX, Where R¹═R²=Methyl,R⁴=Trifluoroethyl, R⁵=H, W=Carbon)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 495 (Structure 51 ofScheme IX, where R¹═R²=methyl, W=carbon) and trifluoroacetaldehyde inplace of Compound 200 and propionaldehyde. Compound 500 was isolated asa white solid: ¹H NMR (400 MHz, CDCl₃) 8.12 (brs, 1H), 6.64 (m, 2H),6.51 (dd, J=2.5, 8.4, 1H), 3.85 (brs, 1H), 3.74 (m, 2H), 2.44 (s, 2H),1.30 (s, 6H).

EXAMPLE 2373,4-Dihydro-4,4-dimethyl-6-(bis-N,N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone(Compound 501, Structure 52 of Scheme IX, Where R¹═R²=Methyl,R⁴═R⁵=Trifluoroethyl, W=Carbon)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using Compound 495 (Structure 51of Scheme IX, where R¹═R²=methyl, W=carbon) and trifluoroacetaldehyde inplace of Compound 200 and paraformaldehyde. Compound 501 was isolated asa white solid: ¹H NMR (400 MHz, CDCl₃) 8.17 (brs, 1H), 6.88 (d, J=2.6,1H), 6.76 (dd, J=2.5, 8.6, 1H), 6.72 (d, J=8.6, 1H), 3.98 (q, J=8.6,4H), 2.48 (s, 2H), 1.31 (s, 6H).

EXAMPLE 2383,4-Dihydro-6-(N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone (Compound502, Structure 52 of Scheme IX, Where R¹═R²═R⁵=H, R⁴=Trifluoroethyl,W=Carbon)

6-Amino-3,4-dihydro-2(1H)-quinolinone (Compound 503, Structure 51 ofScheme IX, Where R¹═R²=H, W=carbon):

To a solution of 3,4-dihdyro-2(1H)-quinolinone (Compound 504, Structure49 of Scheme IX, where R¹═R²=H, W=carbon) (1 g, 6.8 mmol) and conc.Sulfuric acid (15 mL) was added fuming nitric acid (0.3 mL in 3 mL ofconc. Sulfuric acid). Stirred at 0 ° C. for 30 min. then cast into iceto give a yellow precipitate. Filtered, washed with water and dried toafford 1.3 g (100%) of as a white crystalline solid. A solution of theabove solid (200 mg, 1.04 mmol) and DCM (30 mL) was hydrogenated over10% Pd/C (20 mg) at 1 atm and rt. After 15 hrs. filtered through Celiteand concentrated in vacuo to afford 168 mg (100%) of Compound 503 as awhite solid: ¹H NMR (400 MHz, CDCl₃) 7.42 (brs, 1H), 6.53 (m, 3H), 3.52(brs, 2H), 2.87 (t, J=7.1, 2H), 2.58 (t, J=7.1, 2H).

3,4-Dihydro-6-(N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone (Compound502, Structure 52 of Scheme IX, Where R¹═R²═R⁵=H, R⁴=Trifluoroethyl,W=Carbon):

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 503 andtrifluoroacetaldehyde in place of Compound 200 and propionaldehyde.Compound 502 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.79(brs, 1H), 6.62 (d, J=8.5, 1H), 6.51 (m, 2H), 3.74 (q, J=8.9, 2H), 2.90(t, J=7.2, 2H), 2.59 (t, J=7.2, 2H).

EXAMPLE 2393,4-Dihydro-6-(bis-N,N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone(Compound 505, Structure 52 of Scheme IX, Where R¹═R²=H,R⁴═R⁵=Trifluoroethyl, W=Carbon)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using Compound 503 andtrifluoroacetaldehyde in place of Compound 200 and paraformaldehyde.Compound 505 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.86(brs, 1H), 6.76 (m, 2H), 6.68 (d, J=8.5, 1H), 3.98 (q, J=8.6, 4H), 2.94(t, J=7.1, 2H), 2.62 (t, J=7.1, 2H).

EXAMPLE 2405-(bis-N,N-2,2,2-Trifluoroethyl)amino-3,3-spirocyclohexyl-2-indolone(Compound 506, Structure 55 of Scheme X, Where R¹═R²=Trifluoroethyl)

5-Amino-3-spirocyclohexyloxindole (Compound 507, Structure 54 of SchemeX):

This compound was prepared in a similar fashion as that described inExample 1, General Procedures II and III but using3-spirocyclohexyloxindole in place of Compound 202. Compound 507 wasisolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.74 (bs, 1H), 6.86(d, J=1.9, 1H), 6.69 (d, J=7.9, 1H), 6.55 (dd, J=2.2, 8.1, 1H), 3.54(bs, 2H), 1.93-1.76 (mm, 4H), 1.73-1.57 (mm, 6H).

5-(bis-N,N-2,2,2-Trifluoroethyl)amino-3,3-spirocyclohexyl-2-indolone(Compound 506, Structure 55 of Scheme X, Where R¹═R²=Trifluoroethyl):

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using Compound 507 andtrifluoroacetaldehyde in place of Compound 200 and paraformaldehyde.Compound 506 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.52(bs, 1H), 7.11 (s, 1H), 6.84 (s, 2H), 3.95 (q, J=8.7, 4H), 1.97-1.92 (m,2H), 1.89-1.83 (m, 2H), 1.71-1.57 (m, 6H).

EXAMPLE 2417-(bis-N,N-2,2,2-Trifluoroethyl)amino-1,4-benzoxazin-3(4H)-one (Compound508, Structure 57 of Scheme X, Where R¹═R²=Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from 7-amino-1,4-benzoxazin-3(4H)-one(Compound 509, Structure 56 of Scheme X) and trifluoroacetic acid aswhite solid. ¹H NMR (500 MHz, CDCl₃) 8.12 (bs, 1H), 6.72 (d, J=8.8, 1H),6.59 (d, J=2.9, 1H), 6.53 (dd, J=8.8, 2.9, 1H), 4.61 (s, 2H), 3.97 (q,J_(H-F)=8.8, 4H).

EXAMPLE 242 6-(bis-N,N-2,2,2-Trifluoroethyl)amino-2,4-dichloroquinoline(Compound 510 Structure 59 of Scheme X, Where R¹═R²=Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from6-amino-1,4-dichloro-2(1H)-quinolinone (Compound 511, Structure 58 ofScheme X) and trifluoroacetic acid as brown solid. ¹H NMR (CDCl₃, 500MHz) 7.99 (dd, J=1.0, 8.8, 1H), 7.47-7.50 (m, 3H), 4.22, J=8.8, 4H).

EXAMPLE 243 7-Amino-4-trifluoromethyl-2(1H-quinolinone (Compound 512,Structure 61 of Scheme XI, Where R═R¹=H)

A solution of 1,3-phenylenediamine (5.4 g, 50 mmol) and ethyl4,4,4-trifluoroacetoacetate (11 g, 60 mmol) in ethanol (100 mL) washeated at reflux overnight to give rise to a yellow slurry.P-Toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) was added and thereaction mixture was allowed to stir at reflux for additional 24 h. Thereaction was cooled to room temperature to generate a large amount ofsolid. Filtration of the solid followed by washing the solid withmethanol (2×10 mL) afforded Compound 512 as a yellowish solid (8.5 g,75%): ¹H NMR (400 MHz, acetone-d₆) 10.91 (bs, 1H), 7.47 (dq, J=6.7, 2.4,1H), 6.70 (dd, J=6.7, 2.2, 1H), 6.65 (d, J=2.2, 1H), 6.50 (s, 1H), 5.65(bs, 2H).

EXAMPLE 244 7-Propylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound513, Structure 62 of Scheme XI, Where R═R¹═R²=H, R³=Propyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) (100 mg, 0.45 mmol) in place of Compound 200.Compound 513 was isolated in 84% as a yellow solid: ¹H NMR (400 MHz,acetone-d₆) 10.62 (bs, 1H), 7.46 (dq, J=9.0, 1.5, 1H), 6.68 (dd, J=9.0,2.1, 1H), 6.57 (d, J=2.1, 1H), 6.48 (s, 1H), 5.99 (bs, 1H), 3.17 (m,1H), 1.68 (hex, J=7.8, 2H), 1.01 (t, J=7.8, 3H).

EXAMPLE 245 7-Isopropylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 514, Structure 62 of Scheme XI, Where R═R¹═R²=H, R³=Isopropyl)

This compound was prepared in a similar fashion as that described inExample 2, General. Procedure IV but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) (10 mg, 0.045 mmol) and acetone (58 mg, 1.0mmol) in place of Compound 200 and propionaldehyde. Compound 514 wasisolated in 66% as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 10.70 (bs,1H), 7.58(dq, J=9.0, 1.8, 1H), 6.70 (s, 1H), 6.51 (dd, J=9.0, 2.3, 1H),6.31 (d, J=2.3, 1H), 4.12 (d, J=6.0, 1H), 3.73 (m, 1H), 1.26 (d, J=6.2,6H).

EXAMPLE 2467-(2,2-Dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 515, Structure 62 of Scheme XI, Where R═R¹═R²=H,R³=2,2-Dimethylpropyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) (10 mg, 0.045 mmol) and trimethylacetylaldehyde(86 mg, 1.0 mmol) in place of Compound 200 and propionaldehyde. Compound515 was isolated in 60% as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 11.55(bs, 1H), 7.56 (dq, J=9.0, 1.8, 1H), 6.71 (s, 1H), 6.58 (dd, J=9.1, 2.3,1H), 6.42 (d, J=2.3, 1H), 4.30 (t, J=6.0, 1H), 3.00 (d, J=6.0, 1H), 1.02(s, 3H).

EXAMPLE 247 7-(2-Methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 516, Structure 62 of Scheme XI, Where R═R¹═R²=H,R³=2-Methylpropyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) (10 mg, 0.045 mmol) and isobutyraldehyde (72mg, 1.0 mmol) in place of Compound 200 and propionaldehyde. Compound 516was isolated in 67% as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 11.43(bs, 1H), 7.57 (dq, J=9.0, 1.8, 1H), 6.70 (s, 1H), 6.55 (dd, J=9.1, 2.4,1H), 6.38 (d, J=2.4, 1H), 4.34 (t, J=6.2, 1H), 3.04 (t, J=6.3, 1H), 1.01(d, J=6.4, 6H).

EXAMPLE 248 7-Methylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound517, Structure 62 of Scheme XI, Where R═R¹═R²=H, R³=Methyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) (10 mg, 0.045 mmol) and paraformaldehyde (10mg, 0.33 mmol) in place of Compound 200 and propionaldehyde. Compound517 was isolated in 73% as a yellow solid: ¹H NMR (400 MHz, acetone-d₆)10.68 (bs, 1H), 7.46 (dq, J=9.0, 1.5, 1H), 6.66 (dd, J=9.0, 2.1, 1H),6.52 (d, J=2.1, 1H), 6.47 (s, 1H), 5.99 (bs, 1H), 2.88 (d, J=5.0, 3H).

EXAMPLE 249 7-Dimethylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 518, Structure 62 of Scheme XI, Where R═R¹=H, R³═R²=Methyl)

This compound was prepared in a similar fashion as that described inExample 15, General Procedure VIII but using Compound 512 (Structure 61of Scheme XI, where R¹═R=H) (10 mg, 0.045 mmol) in place of Compound200. Compound 518 was isolated in 50% as a yellow solid: ¹H NMR (400MHz, CDCl₃) 11.22 (bs, 1H), 7.63 (dq, J=9.0, 1.5, 1H), 6.72 (s, 1H),6.71 (dd, J=9.0, 2.1, 1H), 6.43 (d, J=2.1, 1H), 3.10 (s, 6H).

EXAMPLE 250 7-Benzylamino-4-trifluoromethyl-2(H1H)-quinolinone (Compound519, Structure 62 of Scheme XI, Where R═R¹═R²=H, R³=Benzyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) and benzaldehyde in place of Compound 200 andpropionaldehyde. Compound 519 was isolated as a yellow solid: ¹H NMR(400 MHz, acetone-d₆) 10.96 (bs, 1H), 7.49 (dq, J=9.0, 1.5, 1H), 7.41(d, J=7.6, 2H), 7.33 (t, J=7.6, 3H), 7.27 (t, J=7.6, 1H), 6.76 (dd,J=9.0, 2.1, 1 H), 6.60 (d, J=2.1, 1H), 4.45 (d, J=5.9, 2H).

EXAMPLE 2517-(2,2,3,3,3-Pentafluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 520, Structure 62 of Scheme XI, Where R═R¹═R²=H,R³=2,2,3,3,3-Pentafluoropropyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) (100 mg, 0.45 mmol) and pentafluoropropionicacid in place of Compound 200 and 2,2-difluoroacetic acid. Compound 520was isolated in 50% as a yellow solid: ¹H NMR (400 MHz, acetone-d₆)10.88 (bs, 1H), 7.58 (dq, J=9.0, 1.5, 1H), 6.87 (dd, J=9.0, 2.1, 1H),6.81 (d, J=2.1, 1H), 6.58 (s, 1H), 6.47 (bs, 1H), 4.14 (td, J=15.5, 6.5,2H).

EXAMPLE 252 7-Butylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound521, Structure 62 of Scheme XI, Where R═R¹═R²=H, R³=Butyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) (10 mg, 0.045 mmol) and butyraldehyde in placeof Compound 200 and propionaldehyde. Compound 521 was isolated in 80% asa yellow solid: ¹H NMR (400 MHz, CDCl₃) 11.40 (bs, 1H), 7.58 (dq, J=9.0,1.5, 1H), 6.72 (s, 1H), 6.58 (dd, J=9.0, 2.1, 1H), 6.39 (d, J=2.1, 1H),4.23 (t, J=6.0, 1H), 3.22 (q, J=6.5, 2H), 1.69-1.42 (m, 4H), 1.0 (t,J=7.3, 3H).

EXAMPLE 253 7-Ethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound522, Structure 62 of Scheme XI, Where R═R¹═R²=H, R³=Ethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) (100 mg, 0.45 mmol) and acetic acid in place ofCompound 200 and 2,2-difluoroacetic acid. Compound 522 was isolated in89% as a yellow solid: ¹H NMR (400 MHz, acetone-d₆) 10.78 (bs, 1H), 7.56(dq, J=9.0, 1.5, 1H), 6.76 (dd, J=9.0, 2.1, 1H), 6.65 (d, J=2.1, 1H),6.57 (s, 1H), 6.02 (bs, 1H), 3.32 (m, 2H), 1.36 (t, J=7.3, 3H).

EXAMPLE 2547-(N-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 523, Structure 62 of Scheme XI, Where R═R¹═R²=H,R³=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) (100 mg, 0.45 mmol) and trifluoroacetic acid inplace of Compound 200 and 2,2-difluoroacetic acid. Compound 523 wasisolated in 50% as a yellow solid: mp 238-239° C.; ¹H NMR (400 MHz,acetone-d₆) 10.95 (bs, 1H), 7.56 (dq, J=9.0, 1.5, 1H), 6.86 (dd, J=9.0,2.1, 1H), 6.80 (d, J=2.1, 1H), 6.60 (s, 1H), 6.50 (bs, 1H), 4.05 (m,2H).

EXAMPLE 255 7-Cyclohexylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 524, Structure 62 of Scheme XI, Where R═R¹═R²=H,R³=Cyclohexyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) and cyclohexanone in place of Compound 200 andpropionaldehyde. Compound 524 was isolated as a yellow solid: ¹H NMR(500 MHz, acetone-d₆) 10.6 (bs, 1H), 7.44 (dd, J=9.3, 2.4, 1H), 6.67(dd, J=9.3, 2.4, 1H), 6.59 (d, J=2.4, 1H), 6.46 (s, 1H), 5.84 (d, J=7.3,1H), 3.39-3.31 (m, 1H), 1.81-1.77 (m, 2H), 1.68-1.64 (m, 1H), 1.46-1.38(m, 2H), 1.32-1.22 (m, 3H).

EXAMPLE 256 7-Cyclopentylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 525, Structure 62 of Scheme XI, Where R═R¹═R²=H,R³=Cycloentyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) and cyclopentanone in place of Compound 200 andpropionaldehyde. Compound 525 was isolated as a yellow solid: ¹H NMR(500 MHz, acetone-d₆) 10.8 (bs, 1H), 7.45 (dd, J=8.8, 2.2, 1H), 6.67(dd, J=8.8, 2.4, 1H), 6.59 (d, J=2.4, 1H), 6.48 (s, 1H), 5.98 (d, J=5.9,1H), 3.90-3.84 (m, 1H), 2.09-2.04 (m, 2H), 1.79-1.71 (m, 2H), 1.68-1.55(m, 4H).

EXAMPLE 257 7-Cyclobutylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 526, Structure 62 of Scheme XI, Where R═R¹═R²=H,R³=Cyclobutyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 512 (Structure 61 ofScheme XI, where R¹═R=H) and cyclobutanone in place of Compound 200 andpropionaldehyde. Compound 526 was isolated as a yellow solid: ¹H NMR(500 MHz, DMSO-d₆) 11.8 (bs, 1H), 7.36 (d, J=9.3, 1H), 6.98 (d, J=5.9,1H), 6.55 (dd, J=9.3, 1.5, 1H), 6.43 (s, 1H), 6.34 (d, J=1.5, 1H),3.85-3.80 (m, 1H), 2.37-2.32 (m, 2H), 1.89-1.83 (m, 2H), 1.78-1.72 (m,2H).

EXAMPLE 2587-(2-Hydroxy-2-methylpropionyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 527, Structure 62 of Scheme XI, Where R═R¹═R²=H,R³=2-Hydroxy-2-methylpropionyl)

To a solution of Compound 512 (Structure 61 of Scheme XI, where R¹═R=H)(12 mg, 0.036 mmol) in THF (2 mL) was added1-chlorocarbonyl-1-methylethyl acetate (10 mg, 0.06 mmol), the mixturewas stirred at room temperature for a few minutes. Triethylamine (10 mg,0.10 mmol) was added and the reaction was stirred for additional 2 h andthen was quenched with 5% NaOH. The mixture was extracted with EtOAc(2×20 mL), washed with brine, and concentrated. Chromatography affordedCompound 527 as a white solid: mp 289-291° C.; ¹H NMR (400 MHz, ODCD₃)8.14 (d, J=2.0, 1H), 7.75 (dq, J=8.9, 2.0, 1H), 7.42 (dd, J=8.9, 2.1,1H), 6.88 (s, 1H), 4.85 (s, 6H).

EXAMPLE 259 7-(Trifluoroacetamido)-4-trifluoromethyl-2(1H)-quinolinone(Compound 528, Structure 62 of Scheme XI, Where R═R¹═R²=H,R³=Trifluoroacetyl)

To a solution of Compound 512 (Structure 61 of Scheme XI, where R¹═R=H)(46 mg, 0.20 mmol) in 1 mL pyridine was added trifluoroacetic anhydride(0.14 mL, 1.0 mmol). After 16 h, the solution was partitioned betweenEtOAc (30 mL) and 1N NaHSO₄ (30 mL). The organic layer was washedsequentially with pH 6.88 phosphate buffer (20 mL) and brine (20 mL),dried over MgSO₄, filtered and concentrated. Flash chromatography (9:1CH₂Cl₂:MeOH) afforded 54 mg (83%) of Compound 528: R_(f) 0.24 (9:1CH₂Cl₂:MeOH); ¹H NMR (400 MHz, acetone-d₆) 11.3 (broad s, 1H), 10.7(broad s, 1H), 8.41 (d, J=1.7, 1H), 7.81 (d, J=8.9, 1H), 7.58 (dd,J=9.0, 1.8, 1H), 6.92 (s, 1H).

EXAMPLE 260 1-Methyl-7-methylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 529, Structure 63 of Scheme XI, Where R═R¹═R²=H, R³═R⁴=Methyl)

This compound was prepared in a similar fashion as that described inExample 92, General Procedure X from Compound 517 (Structure 62 ofScheme XI, where R═R¹═R²=H, R²=methyl). Compound 529 was isolated as ayellow solid: ¹H NMR (400 MHz, CDCl₃) 7.63 (dq, J=9.0, 1.5, 1H), 6.78(s, 1H), 6.57 (dd, J=9.0, 2.1, 1H), 6.37 (d, J=2.1, 1H), 4.42 (bs, 1H),3.69 (s, 3H), 2.97 (d, J=5.2, 3H).

EXAMPLE 261 1-Methyl-7-dimethylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 530, Structure 63 of Scheme XI, Where R═R¹═H, R²═R³═R⁴=Methyl)

This compound was prepared in a similar fashion as that described inExample 92, General Procedure X from Compound 518 (Structure 62 ofScheme XI, where R═R¹═H, R³═R²=methyl). Compound 530 was isolated as ayellow solid: ¹H NMR (400 MHz, CDCl₃) 7.66 (dq, J=9.0, 1.5, 1H), 6.78(s, 1H), 6.72(dd, J=9.0, 2.1, 1H), 6.39 (d, J=2.1, 1H), 3.70 (s, 3H),3.13 (s, 6H).

EXAMPLE 2621-Methyl-7-(N-methyl-N-isopropylamino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 531, Structure 63 of Scheme XI, Where R═R¹=H, R²═R⁴=Methyl,R³=Isopropyl)

This compound was prepared in a similar fashion as that described inExample 92, General Procedure X from Compound 514 (Structure 62 ofScheme XI, where R═R¹═R²=H, R³=isopropyl). Compound 531 was isolated asa yellow solid: ¹H NMR (500 MHz, CDCl₃) 7.65 (dd, J=9.3, 2.4, 1H), 6.79(dd, J=9.3, 2.4, 1H), 6.77 (s, 1H), 6.47 (d, J=2.4, 1H), 4.27-4.23 (m,1H) 3.70 (s, 3H), 2.89 (s, 3H), 1.26 (d, J=6.3, 6H).

EXAMPLE 2631-Methyl-7-(2,2,2-trifluoromethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 532 Structure 63 of Scheme XI, Where R═R¹═R²=H, R⁴=Methyl,R³=Trifluoromethyl)

This compound was prepared in a similar fashion as that described inExample 92, General Procedure X from Compound 523 (Structure 62 ofScheme XI, where R═R¹═R²=H, R³=2,2,2-trifluoroethyl). Compound 532 wasisolated as a yellow solid: ¹H NMR (500 MHz, CDCl₃+DMSO-d₆) 7.64 (dd,J=8.8, 2.0, 1H), 6.84 (s, 1H), 6.71 (dd, J=8.8, 2.0, 1H), 6.62 (d,J=2.0, 1H), 5.96 (bt, J=6.8, 1H), 3.93-3.86 (m, 2H), 3.68 (s, 3H).

EXAMPLE 2643-Fluoro-7-(2,2,2-trifluoromethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 533, Structure 62 of Scheme XI, Where R=Fluoro, R¹═R²=H,R³=Trifluoromethyl)

3-Fluoro-7-amino-4-trifluoromethyl-2(H1)-quinolinone (Compound 534,Structure 61 of Scheme XI, Where R=Fluoro, R¹=H):

This compound was prepared in a similar manner as that described inExample 1, General Procedures I, II and III but using ethyl2,4,4,4-tetrafluoroacetoacetate hydrate in place of ethyl4,4,4-trifluoroacetoacetate. Compound 534 was isolated as a white solid:¹H NMR (500 MHz, DMSO-d₆) 12.4 (bs, 1H), 7.39 (dd, J=8.8, 2.0, 1H), 6.64(dd, J=9.3, 1.9, 1H), 6.50 (d, J=2.4, 1H), 6.05 (bs, 2H).

3-Fluoro-7-(2,2,2-trifluoromethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 533, Structure 62 of Scheme XI, Where R=Fluoro, R¹═R²=H,R³=Trifluoromethyl):

Compound 534 was dissolved in trifluoroacetic acid (15 mL) and heated to60° C. for 2 h, cooled to room temperature where sodium borohydride (350mg, 9.25 mmol, 5.0 equiv) was carefully added in portions to thereaction mixture. After complete addition of sodium borohydride thereaction mixture was allowed to stir for 16 h, poured over ice andneutralized to pH 7 with NaOH pellets. A white precipitate was filteredfrom the aqueous solution, redissolved in EtOAc (200 mL), washed withwater (25 mL), brine (25 mL), dried (MgSO₄), filtered and concentratedunder reduced pressure to yield an off white solid. Purification byre-crystallization (MeOH) afforded 135 mg (22%) of Compound 533 as awhite solid: ¹H NMR (400 MHz, acetone-d₆) 11.18 (bs, 1H), 7.58 (dd,J=8.9, 2.1, 1H), 6.90 (dd, J=9.0, 2.2, 1H), 6.81 (d, J=2.3, 1H), 6.40(bm, 1H), 4.04 (m, 2H).

EXAMPLE 2653-Fluoro-7-isopropylamino-4-trifluoromethyl-2(1H1)-quinolinone (Compound535, Structure 62 of Scheme XI, Where R=Fluoro, R¹═R²=H, R³=Isopropyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 534 (Structure 61 ofScheme XI, where R¹=H, R=fluoro) and acetone in place of Compound 200and propionaldehyde. Compound 535 was isolated as a yellow solid: ¹H NMR(500 MHz, acetone-d₆) 11.0 (bs, 1H), 7.49 (d, J=9.1, 1H), 6.72 (d,J=9.1, 1H), 6.59 (t, J=2.4, 1H), 6.86 (s, 1H), 5.69 (bs, 1H), 3.71-3.67(m, 1H), 1.24 (d, J=6.3, 6H).

EXAMPLE 2663-Fluoro-7-cyclopentylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 536, Structure 62 of Scheme XI, Where R=Fluoro, R¹═R²=H,R³=Cyclopentyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 534 (Structure 61 ofScheme XI, where R¹=H, R=fluoro) and cyclopentanone in place of Compound200 and propionaldehyde. Compound 536 was isolated as a yellow solid: ¹HNMR (500 MHz, acetone-d₆) 11.1 (bs, 1H), 7.49 (dd, J=9.3, 2.4, 1H), 6.73(dd, J=9.3, 2.4, 1H), 6.61 (d, J=2.4, 1H), 5.88 (bs, 1H), 3.87-3.83 (m,1H), 2.08-1.98 (m, 2H), 1.76-1.56 (m, 6H).

EXAMPLE 2673-Fluoro-7-cyclohexylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound537, Structure 62 of Scheme XI, Where R=Fluoro, R¹═R²=H, R³=Cyclohexyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 534 (Structure 61 ofScheme XI, where R¹=H, R=fluoro) and cyclocyclohexanone in place ofCompound 200 and propionaldehyde. Compound 537 was isolated as a yellowsolid: ¹H NMR (500, acetone-d₆) 11.1 (bs, 1H), 7.48 (dd, J=9.3, 2.4,1H), 6.73 (dd, J=9.3, 2.4, 1H), 6.61 (d, J=2.4, 1H), 5.74 (d, J=7.3,1H), 3.36-3.31 (m, 1H), 1.81-1.77 (m, 2H), 1.67-1.64 (m, 1H), 1.43-1.37(m, 2H), 1.31-1.21 (m, 3H).

EXAMPLE 2683-Fluoro-7-cyclobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound538, Structure 62 of Scheme XI, Where R=Fluoro, R¹═R²=H, R³=Cyclobutyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 534 (Structure 61 ofScheme XI, where R¹=H, R=fluoro) and cyclocyclobutanone in place ofCompound 200 and propionaldehyde. Compound 538 was isolated as a yellowsolid: ¹H-NMR (500, acetone-d₆) 12.3 (bs, 1H), 7.41 (dd, J=8.8, 2.4,1H), 6.88 (d, J=5.9, 1H), 6.63 (dd, J=8.8, 2.4, 1H), 6.37 (d, J=2.4,1H), 3.84-3.80 (m, 1H), 2.38-2.32 (m, 2H), 1.91-1.83 (m, 2H), 1.80-1.72(m, 2H).

EXAMPLE 269 3-Fluoro-7-propylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 539, Structure 62 of Scheme XI, Where R=Fluoro, R¹═R²=H,R³=Propyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 534 (Structure 61 ofScheme XI, where R¹=H, R=fluoro) in place of Compound 200. Compound 539was isolated as a yellow solid: ¹H NMR (500, acetone-d₆) 11.0 (bs, 1H),7.50 (dd, J=8.8, 2.2, 1H), 6.75 (dd, J=8.8, 2.2, 1H), 6.58 (d, J=2.4,1H), 5.89 (bs, 1H), 3.18-3.14 (m, 2H), 1.70-1.65 (m, 2H), 0.99 (t,J=7.3, 3H).

EXAMPLE 2703-Fluoro-1-methyl-7-(N-methyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 540, Structure 63 of Scheme XI, Where R=Fluoro, R¹=H,R²═R⁴=Methyl, R³=Isopropyl)

This compound was prepared in a similar fashion as that described inExample 92, General Procedure X from Compound 535 (Structure 62 ofScheme XI, where R=fluoro, R¹═R²=H, R³=isopropyl). Compound 540 wasisolated as a yellow solid: ¹H NMR (500 MHz, acetone-d₆) 7.69 (dd,J=9.3, 2.4, 1H), 6.94 (dd, J=9.3, 2.4, 1H), 6.67 (d, J=2.4, 1H),4.43-4.37 (m, 1H), 3.94 (s, 3H), 3.71 (s, 3H), 1.23 (d, J=6.3, 6H).

EXAMPLE 2713-Fluoro-1-methyl-7-propylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 541, Structure 63 of Scheme XI, Where R=Fluoro, R¹═R²=H,R⁴=Methyl, R³=Propyl)

This compound was prepared in a similar fashion as that described inExample 92, General Procedure X from Compound 539 (Structure 62 ofScheme XI, where R=fluoro, R¹═R²=H, R=propyl). Compound 541 was isolatedas a yellow solid: ¹H NMR (400 MHz, CDCl₃) 7.63 (dd, J=9.1, 1.9, 1H),6.62 (dd, J=9.1, 2.1, 1H), 6.38 (d, J=2.1, 1H), 4.23 (bs, 1H), 3.23 (s,3H), 3.19 (t, J=7.1, 6H), 1.75-1.67 (m, 2H), 1.05 (t, J=7.4, 3H).

EXAMPLE 272 6-Fluoro-7-amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 542, Structure 63 of Scheme XI, where R¹=Fluoro, R=H)

This compound was prepared in a similar manner as that described inExample 243 but using 4-fluoro-1,3-phenylenediamine (Structure 60 ofScheme XI, where R¹=fluorine) in place of 1,3-phenylenediamine. Compound542 was isolated as a yellow solid: ¹H NMR (400 MHz, CD₃OD) 7.35 (d,J=9.2, 1H), 6.71 (d, J=7.5, 1H), 6.65 (s, 1H).

EXAMPLE 273 6-Fluoro-7-propylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 543, Structure 62 of Scheme XI, Where R¹=Fluoro, R═R²=H,R³=Propyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 542 (Structure 61 ofScheme XI, where R¹=fluoro, R=H) in place of Compound 200. Compound 543was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 7.49 (d, J=7.5,1H), 6.78 (s, 1H), 6.40 (d, J=7.5, 1H), 4.51 (br t, 1H), 3.22 (m, 2H),1.74 (q, J=7.3, 2H), 1.07 (t, J=7.3, 3H).

EXAMPLE 274 6-Fluoro-7-isobutylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 544, Structure 62 of Scheme XI, Where R¹=Fluoro, R═R²=H,R³=Isobutyl)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 542 (Structure 61 ofScheme XI, where R¹=fluoro, R=H) and isobutyraldehyde in place ofCompound 200 and propionaldehyde. Compound 544 was isolated as a yellowsolid: ¹H NMR (400 MHz, CD₃OD) 7.30 (d, J=7.5, 1H), 6.61 (s, 1H), 6.59(d, J=7.5, 1H), 3.05 (d, J=7.3, 2H), 2.00 (m, 1H), 1.00 (d, J=6.6, 6H).

EXAMPLE 2756-Fluoro-1-methyl-7-propylamino-4-trifluoromethyl-2(H1)-quinolinone(Compound 545, Structure 63 of Scheme XI, Where R¹=Fluoro, R═R²=H,R⁴=Methyl, R³=Propyl)

This compound was prepared in a similar fashion as that described inExample 92, General Procedure X from Compound 543 (Structure 62 ofScheme XI, where R=fluoro, R═R²=H, R³=propyl). Compound 545 was isolatedas a yellow solid: ¹H NMR (400 MHz, CD₃OD) 7.34 (d, J=9.2, 1H), 6.73 (s,1H), 6.66 (d, J=7.6, 1H), 3.74 (s, 3H), 3.31 (m under solvent peak, 2H),1.75 (m, 2H), 1.05 (t, J=7.4, 3H).

EXAMPLE 2766-Fluoro-1-methyl-7-(N-methyl-N-propylamino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 546, Structure 63 of Scheme XI, Where R²=Fluoro, R=H,R²═R⁴=Methyl, R³=Propyl)

This compound was prepared in a. similar fashion as that described inExample 92, General Procedure X from Compound 543 (Structure 62 ofScheme XI, where R¹=fluoro, R═R²=H, R³=propyl). Compound 546 wasisolated as a yellow solid: ¹H NMR (400 MHz, CD₃OD) 7.39 (d, J=15.3,1H), 6.79 (s under d, 2H), 3.75 (s, 3H), 3.43 (m, 2H), 3.10 (s, 3H),1.70 (m, 2H), 0.95 (t, J=7.4, 3H).

EXAMPLE 277 7-Amino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 547, Structure 61 of Scheme XI, Where R¹=Methyl, R=H)

This compound was prepared in a similar manner as that described inExample 243 but using 2,4-diaminotoluene (Structure 60 of Scheme XI,where R¹=methyl) in place of 1,3-phenylenediamine. Compound 547 wasisolated as a white solid: ¹H NMR (400 MHz, DMSO-d₆), 11.00 (br s, 1H),7.21 (s, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 2.10 (s, 3H).

EXAMPLE 278 7-Isobutylamino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 548, Structure 62 of Scheme XI, Where R¹=Methyl, R²=Isobutyl,R═R³=H)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 547 (Structure 61 ofScheme XI, where R¹=methyl, R=H) and isobutyraldehyde in place ofCompound 200 and propionaldehyde. Compound 548 was isolated as a yellowsolid: ¹H NMR (400 MHz, DMSO-d₆) 11.00 (br s, 1H), 7.22 (s, 1H), 6.45(s, 1H), 6.40 (s, 1H), 6.05 (br t, 1H), 2.92 (m, 2H), 2.15 (s, 3H), 1.99(m, 1H), 0.93 (d, J=6.6, 6H).

EXAMPLE 279 7-Propylamino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 549, Structure 62 of Scheme XI, Where R¹=Methyl, R²=Propyl,R═R³=H)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 547 (Structure 61 ofScheme XI, where R¹=methyl, R=H) in place of Compound 200. Compound 549was isolated as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 10.60 (br s,1H), 7.42 (s, 1H), 6.70 (s, 1H), 6.33 (s, 1H), 4.05 (br t, 1H), 3.20 (m,2H), 2.20 (s, 3H), 1.74 (q, J=7.4, 2H), 1.06 (t, J=7.4, 3H).

EXAMPLE 2807-(1,1-Dimethyl-3-oxobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 550, Structure 64 of Scheme XII)

A solution of Compound 512 (Structure 61a of Scheme XII) (460 mg, 2.0mmol) and a catalytic amount of acetic acid in acetone (5 mL) wasstirred at room temperature overnight. Removal of solvent andchromatography of the reaction mixture afforded Compound 550 (100 mg,15%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 11.03 (bs, 1H), 7.57(dq, J=9.0, 1.8, 1H), 6.73 (d, J=2.1, 1H), 6.72 (s, 1H), 6.62 (dd,J=9.0, 2.1, 1H), 4.90 (bs, 1H), 2.89 (s, 2H), 2.14 (s, 3H), 1.52 (s,6H).

EXAMPLE 2817-(1,1,3-Trimethyl-3-hydroxybutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 551, Structure 65 of Scheme XII)

To a solution of Compound 550 (Structure 61a of Scheme XII) (10 mg,0.031 mmol) in THF at −78° C. was added MeLi (0.1 mL, 1.4 M in ether)and resulting mixture was stirred for 30 min. and quenched with water.Extraction with EtOAc followed by chromatography afforded Compound 551(5.0 mg, 49%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 11.40 (bs, 1H),7.53 (dq, J=9.0, 1.8, 1H), 6.71 (d, J=2.1, 1H), 6.70 (s, 1H), 6.60 (dd,J=9.0, 2.1, 1H), 5.50 (bs, 1H), 2.18 (s, 1H), 1.97 (s, 2H), 1.55 (s,6H), 1.38 (s, 6H).

EXAMPLE 2827-(1,1,3-Trimethyl-3-butenylamino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 552, Structure 66 of Scheme XII)

A solution of Compound 551 (Structure 65 of Scheme XII) (7.0 mg, 0.020mmol) in acetone was treated with catalytic amount of acetic acid atroom temperature overnight and standard work-up provided Compound 552(2.7 mg, 41%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 11.30 (bs, 1H),7.61 (dq, J=8.8, 1.5, 1H), 6.85 (d, J=2.1, 1H), 6.85 (s, 1H), 6.75 (dd,J=8.8, 2.1, 1H), 5.21 (s, 1H), 4.39 (s, 1H), 2.73 (d, J=15.4, 1H), 2.17(d, J=15.4, 1H), 1.78 (s, 3H), 1.68 (s, 3H), 1.50 (s, 3H).

EXAMPLE 2837-(1-Phenylaminocarbonylisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 553, Structure 69 of Scheme XIII)

7-Amino-2-ethoxy-4-trifluoromethylquinoline (Compound 554, Structure 67of Scheme XIII):

This compound was prepared in a similar method as that described inExample 243. A solution of 1,3-phenylenediamine (5.4 g, 50 mmol) andethyl 4,4,4-trifluoroacetoacetate (11 g, 60 mmol) in ethanol (100 mL)was heated at reflux overnight to give rise to a yellow slurry.P-Toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) was added and thereaction mixture was allowed to stir at reflux for additional 24 h. Thereaction was cooled to room temperature to generate a large amount ofsolid. Filtration from the solid (Compound 512 as major product) andremoval solvent provided the crude mixture. Chromatography of themixture on a silica gel column afforded Compound 554 (1.4 g, 11%) as ayellow solid: ¹H NMR (400 MHz, acetone-d₆) 7.70 (dq, J=9.5, 2.1, 1H),7.05-7.01 (m, 2H), 6.86 (s, 1H), 5.44 (bs, 2H), 4.47 (q, J=7.0, 2H),1.39 (t, J=7.0, 3H).

7-(1-Phenylaminocarbonylisopropyl)amino-2-ethoxy-4-trifluoromethylquinoline(Compound 555, Structure 68 of Scheme XIII):

To a flask charged with NaH (40 mg, 60% in mineral oil, 1.0 mmol) in THF(2 mL) was added a solution of Compound 554 (128 mg, 0.5 mmol) in THF (2mL). A solution of N-phenyl-2-bromobutyratamide (121 mg, 0.5 mmol) inTHF (2 mL) was introduced slowly in 15 min. and the reaction mixture wasstirred at room temperature for 1 h, then quenched with water andextracted with EtOAc. Removal of solvent and chromatography of the cruderesidue afforded Compound 555 as a white solid: ¹H NMR (400 MHz, CDCl₃)8.74 (s, 1H), 7.81 (dq, J=9.5, 2.1, 1H), 7.50 (d, J=7.5, 2H); 7.31 (t,J=7.5, 2H), 7.11 (t, J=7.5, 1H), 7.00 (d, J=2.5, 1H), 6.96 (s, 1H), 6.85(dd J=9.5, 2.5, 1H), 4.47 (q, J=7.2, 2H), 1.67 (s, 6H), 1.39 (t, J=7.2,3H).

7-(1-Phenylaminocarbonylisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 553, Structure 69 of Scheme XIII):

Treatment of Compound 555 with hydriodic acid (57% aqueous) at 60° C.for 2 h and standard work-up provided Compound 553 as a yellow solid: ¹HNMR (400 MHz, CDCl₃) 11.10 (bs, 1H), 7.61 (dq, J=9.5, 2.1, 1H), 7.48 (d,J=7.5, 2H), 7.27 (t, J=7.5, 2H), 7.11 (t, J=7.5, 1H), 6.78 (s, 1H), 6.61(dd, J=9.5, 2.5, 1H), 6.54 (d, J=2.5, 1H), 1.64 (s, 6H).

EXAMPLE 2847-(2-Hydroxy-1,1-dimethylethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 556, Structure 72 of Scheme XIII)

7-(N-Methyl-N-1-Phenylaminocarbonylisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 557, Structure 70 of Scheme XIII):

To a flask charged with NaH (80 mg, 60% in mineral oil, 2.0 mmol) in THF(3 mL) was added a solution of Compound 554 (Structure 67 of SchemeXIII) (256 mg, 1.0 mmol) in THF (3 mL). A solution ofN-phenyl-2-bromobutyratamide (242 mg, 1.0 mmol) in THF (4 mL) wasintroduced slowly in 15 min. and the reaction mixture was stirred atroom temperature for 1 h. The reaction mixture was treated withiodomethane (0.3 mL, 4.5 mmol) and stirred for additional 1 h, thenquenched with water and extracted with EtOAc. The crude mixture wastreated with hydriodic acid at 40° C. for 3 h and quenched with 10%NaOH. Extraction with EtOAc and removal of solvent provided the crudeproduct. Purification by chromatography afforded Compound 557 as a whitesolid (220 mg, 50%).

7-(N-2-Formyl-2-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 558, Structure 71 of Scheme XIII) and7-(2-Hydroxy-1,1-dimethylethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 556, Structure 72 of Scheme XIII):

Compound 557 (200 mg, 0.45 mmol) in THF (5 mL) was treated with DIBAL-H(1.5 mL, 1.0 M in toluene) at −60° C. for 1 h. Standard work-up followedby chromatography afforded Compound 558 (50 mg, 36%) and Compound 556(70 mg, 51%). Compound 556 was isolated as a yellow solid: ¹H NMR (400MHz, acetone-d₆) 7.42 (dq, J=8.8, 1.9, 1H), 6.85 (d, J=2.1, 1H), 6.72(dd, J=8.8, 2.1, 1H), 6.48 (s, 1H), 5.54 (s, 1H), 3.60 (s, 2H), 1.86 (s,6H).

EXAMPLE 2857-(1,1-Dimethylallyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound559, Structure 73 of Scheme XIII)

To a mixture of Ph₃PCH₂Br—HCl (72 mg, 0.20 mmol) and NaN(SiMe₃)₂ (0.20mL, 1.0 M in THF) in THF (3 mL) at room temperature was added a THFsolution of Compound 558 (Structure 71 of Scheme XIII) (15 mg, 0.050mmol) and the resulting mixture was stirred for 1 h. Standard work-upfollowed by chromatography afforded Compound 559 (10 mg, 83%) as ayellow oil: 1H NMR (400 MHz, CDCl₃) 11.71 (bs, 1H), 7.52 (dq, J=8.8,1.5, 1H), 6.70 (s, 1H), 6.63 (dd, J=9.1, 2.2, 1H), 6.60 (d, J=2.2, 1H),5.96 (dd, J=17.4, 10.6, 1H), 5.27 (d, J=17.4, 1H), 5.21 (d, J=10.6, 1H),4.44 (s, 1H), 1.46 (s, 6H).

EXAMPLE 2867-(1,1-Dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 560, Structure 74 of Scheme XIII)

A solution of Compound 285 (Structure 73 of Scheme XIII) (5.0 mg, 0.017mmol) in EtOAc was hydrogenated in the presence of a catalytic amount10% Pd/C to afforded Compound 560 (3.0 mg, 60%) as a yellow oil: ¹H NMR(400 MHz, CDCl₃) 11.71 (bs, 1H), 7.53 (dq, J=8.8, 1.5, 1H), 6.70 (s,1H), 6.61 (dd, J=9.1, 2.2, 1H), 6.57 (d, J=2.2, 1H), 4.20 (bs, 1H), 1.78(q, J=7.4, 2H), 1.39 (s, 6H), 0.90 (t, J=7.4, 3H).

EXAMPLE 2877-(1-Methyl-1-acetylenylpropyl)amino]-4-(trifluoromethyl)-2(1H)-quinolinone(Compound 561, Structure 75 of Scheme XIV)

To a mixture of Compound 512 (Structure 61a of Scheme XIV) (1.8 g, 8.0mmol), CuCl (40 mg, 0.40 mmol) in 50 mL THF was added triethylamine(0.89 g, 8.8 mmol) and 3-acetoxy-3-methyl-1-pentyne (1.1 g, 8.0 mmol).After 4 h, the mixture was partitioned between EtOAc (60 mL) and sat'dNH₄Cl (60 mL), and the aqueous layer was extracted with EtOAc (60 mL).The organic layers were washed with brine, dried over MgSO₄, filtered,and concentrated. Flash chromatography (1:1:1 EtOAc:hexanes:CH₂Cl₂)afforded 0.31 g (13%) of Compound 561 as a yellow solid: R_(f) 0.30(1:1:1 EtOAc:hexanes:CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) 12.1 (bs, 1H),7.55-7.65 (m, 1H), 6.93 (dd, J=9.0, 2.3, 1H), 6.88 (d, J=2.2, 1H), 6.75(s, 1H), 4.36 (s, 1H), 2.49 (s, 1H), 1.80-2.00 (m, 2H), 1.60 (s, 3H),1.08 (t, J=7.4, 3H).

EXAMPLE 2887-(1-Ethyl-1-methylpropyl)amino-4-(trifluoromethyl)-2(1H)-quinolinone(Compound 562, Structure 76 of Scheme XIV)

A solution of Compound 561 (Structure 75 of Scheme XIV) (16 mg, 0.052mmol) in EtOAc/EtOH (2:1) was hydrogenated in the presence of 10% Pd—C(2.4 mg, 15 wt %) to afford 10 mg (63%) of Compound 562 as a yellowfoam: R_(f) 0.30 (1:1:1 EtOAc:hexanes:CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃)12.3 (bs, 1H), 7.48-7.56 (m, 1H), 6.70 (s, 1H), 6.58-6.65 (m, 2H), 4.14(broad s, 1H), 1.76-1.90 (m, 2H), 1.62-1.74 (m, 2H), 1.29 (s, 3H), 0.87(t, J=7.4, 3H).

EXAMPLE 2898-Methyl-7-(3-methyl1-2-butenyl)amino-4-(trifluoromethyl)-2(1H)-quinolinone(Compound 563, Structure 79 of Scheme XV, Where R=3-Methyl-2-butenyl)

2-(tert-Butyloxycarbamoyl)-6-(3-methyl-2-butenyl)aminotoluene (Compound564, Structure 77 of Scheme XV, R=3-Methyl-2-butenyl):

To an oven-dried 25-mL r.b. flask containing2-amino-6-(tert-butyloxycarbamoyl)toluene (0.50 g, 2.3 mmol) in 10 mLglacial acetic acid at room temperature was added 3-methyl-2-butenal(senecialdehyde, 0.43 mL, 4.5 mmol, 2.0 equiv) and sodiumcyanoborohydride (0.70 g, 11 mmol, 5.0 equiv), and the mixture wasallowed to stir for 6 h. The mixture was then neutralized to pH 8 withthe careful addition of saturated NaHCO₃. The mixture was then extractedwith EtOAc (2×40 mL), and the combined organic layers were washed withbrine, dried (Na₂SO₄), and concentrated under reduced pressure.Purification by flash chromatography (hexanes:EtOAc, 10:1 to 4:1gradient) afforded 611 mg (94%) of Compound 564 as a white solid: ¹H NMR(400 MHz, CDCl₃) 7.09 (t, 1H, J=8.0, 4-H), 6.96 (br d, 1H, J=8.0, 3-H),6.46 (d, 1H, J=8.1, 5-H), 6.18 (br s, 1H, CONH), 5.36 (t, 1H, J=6.7,C═CH), 3.70 (d, 2H, J=6.7, NHCH₂CH═C), 3.40 (br s, 1H, ArNHCH₂), 2.00(s, 3H, 1-CH₃), 1.76 and 1.71 [2s, 2×3H, CH═C(CH₃)₂], 1.50 [s, 9H,(CH₃)₃CO].

2-Amino-6-(3-methyl-2-butenyl)aminotoluene (Compound 565, Structure 78of Scheme XV, R=3-Methyl-2-butenyl):

Treatment of Compound 564 with TFA removed the tert-butoxy protectiongroup to give Compound 565 in high yield.

8-Methyl-7-(3-methyl-2-butenyl)amino-4-(trifluoromethyl)-2(1H)-quinolinone(Compound 563, Structure 79 of Scheme XV, Where R=3-Methyl-2-butenyl):

This compound was prepared in a similar fashion as that described inExample 243, but using Compound 565 (611 mg, 2.10 mmol) in place of1,3-phenylenediamine. Compound 563 (261 mg, 40%) was isolated as ayellow solid: ¹H NMR (400 MHz, CDCl₃) 9.12 (br s, 1H, CONH), 7.61 (br d,1H, J=7.6, 5-H), 6.71 (s, 1H, 7-H), 6.68 (d, 1H, J=9.1, 6-H), 5.34 (t,1H, J=5.9, C═CH), 4.03 (br s, 1H, ArNHCH₂), 3.84 (t, 2H, J=5.8,NHCH₂CH═C), 2.13 (s, 3H, 8-CH₃), 1.79 and 1.75 [2s, 2×3H, CH═C(CH₃)₂].

EXAMPLE 2908-Methyl-7-(3-methylbutyl)amino-4-(trifluoromethyl)-2(1H)-quinolinone(Compound 566, Structure 79 of Scheme XV Where R=3-Methylbutyl)

To an oven-dried 25-mL r.b. flask containing Compound 289 (Structure 79of Scheme XV, where R=3-methyl-2-butenyl) (74 mg, 0.24 mmol) in 2 mL1,2-dichloroethane was added 0.3 mL TFA and 0.5 mL triethylsilane, andthe mixture was heated to reflux for 8 h. Upon cooling to rt, themixture was added to 5 mL saturated NaHCO₃ and extracted with 10 mLEtOAc. The organic layer was washed with brine, dried (Na₂SO₄), andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, hexanes/EtOAc, 4:1 to 0:1 gradient),affording 28 mg (37%) of Compound 566 as a fluorescent yellow solid: ¹HNMR (400 MHz, CDCl₃) 9.09 (br s, 1H, CONH), 7.61 (br d, 1H, J=7.6, 5-H),6.70 (s, 1H, 7-H), 6.69 (d, 1H, J=9.1, 6-H), 3.99 (br s, 1H, (ArNHCH₂),3.11 [t, 2H, J=6.8, NHCH₂CH₂CH(CH₃)₂], 2.11 (s, 3H, 8-CH₃), 1.7-1.4 [m,3H, NHCH₂CH₂CH(CH₃)₂], 0.98 [d, 2×3H, J=6.7, CH(CH₃)₂].

EXAMPLE 291 8-Methyl-7-propylamino-4-(trifluoromethyl)-2(1H)-quinolinone(Compound 567, Structure 79 of Scheme XV, Where R=Propyl)

3-Amino-2-methyl-N-propylaminobenzene (Compound 568, Structure 78 ofScheme XV, Where R=Propyl):

To a solution of 2-methyl-3-nitroaniline (0.5 g, 3.3 mmol) and MeOH (20mL) was added propionaldehyde (2.3 mL, 33 mmol), AcOH (1.9 mL, 33 mmol),and NaBH₃CN (2 g, 33 mmol). Reaction was stirred at rt for 2 hours thenquenched with H₂O and concentrated in vacuo. Diluted with EtOAc (20 mL)and adjusted to pH=7 with saturated NaHCO₃. Washed organic layer withH₂O (3×10 mL) and brine (3×10 mL), dried (Na₂SO₄) and concentrated invacuo. The crude product was purified by flash chromatography (5%EtOAc/hex) to afford 0.7 g of the 2-methyl-3-nitro-N-propylaminobenzene.A solution of the product and EtOAc (25 mL) was hydrogenated over 10%Pd/C (70 mg) at rt and 1 atm. After 15 hours filtered reaction mixturethrough a pad of Celite and concentrated the filtrate to afford thedesired Compound 568 (0.10 g) as yellow oil.

Compound 568 was dissolved in EtOH (7 mL) and treated withethyl-4,4,4-trifluoromethylacetoacetate (0.11 mL). This reaction mixturewas heated to reflux for 15 hrs. Concentrated in vacuo and purified byflash chromatography (50% EtOAc/hex) to afford the tertiary alcohol (100mg). The tertiary alcohol was dissolved in toluene and treated withp-TsOH (50 mg) and the reaction was heated to reflux for 15 hrs. Thereaction mixture was concentrated in vacuo to afford a light red solidwhich was then washed with EtOH to afford 48 mg (5% overall yield) ofCompound 567 as a white solid: ¹H NMR (400 MHz, CD₃OD) 7.56 (m, 1H),6.78 (d, J=9.2, 1H), 6.56 (s, 1H), 3.27 (m under solvent peak, 2H), 2.20(3H), 1.68 (m, 2H), 1.01 (t, J=7.4, 3H).

EXAMPLE 2928-Methyl-7-isobutylamino-4-(trifluoromethyl)-2(1H)-quinolinone (Compound569, Structure 79 of Scheme XV, Where R=Isobutyl)

3-Amino-2-methyl-N-isobutylaminobenzene (Compound 570, Structure 78 ofScheme XV, Where R=Isobutyl):

To a solution of 2-methyl-3-nitroaniline (Structure 28b of Scheme XV)(0.5 g, 3.3 mmol) and MeOH (20 mL) was added isobutyraldehyde (3 mL, 33mmol), AcOH (1.9 mL, 33 mmol), and NaBH₃CN (2 g, 33 mmol). Reaction wasstirred at rt for 2 hours then quenched with H₂O and concentrated invacuo. Diluted with EtOAc (20 mL) and adjusted to pH=7 with saturatedNaHCO₃. Washed organic layer with H₂O (3×10 mL) and brine (3×10 mL),dried (Na₂SO₄) and concentrated in vacuo. The crude product was purifiedby flash chromatography (5% EtOAc/hex) to afford 0.9 g of theN-isobutylamino-2-methyl-3-nitrobenzene. A solution of the product andEtOAc (25 mL) was hydrogenated over 10% Pd/C (90 mg) at room temperatureand 1 atm. After 15 hours filtered reaction mixture through a pad ofCelite and concentrated the filtrate to afford Compound 570 (0.45 g) asa white solid.

Compound 570 (100 mg) was dissolved in EtOH (7 mL) and treated withethyl-4,4,4-trifluoromethylacetoacetate (0.1 mL). This reaction mixturewas heated to reflux for 15 hrs. Concentrated in vacuo and purified byflash chromatography (50% EtOAc/hex) to afford the tertiary alcoholintermediate. The tertiary alcohol was dissolved in toluene (7 mL) andtreated with p-TsOH (10 mg) and the reaction was heated to reflux for 15hrs. The reaction mixture was concentrated in vacuo then purified byflash chromatography (10% EtOAc/hexane to 100% EtOAc gradient) to afford112 mg (67%) of Compound 569 as a white solid: ¹H NMR (400 MHz, CD₃OD)7.65 (d, J=9.2, 1H), 6.96 (d, J=9.2, 1H), 6.73 (s, 1H), 3.17 (d, J=7.1,2H), 2.20 (s, 3H), 1.02 (d, J=6.7, 6H).

EXAMPLE 2937-Amino-6-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-2(1H)-quinolinone(Compound 571, Structure 83 of Scheme XVI)

2,4-Dinitrophenyl-(2,2,2-trifluoroethyl)ether (Compound 572, Structure81 of Scheme XVI):

In a 100 mL flask, a solution of 2,4-dinitrofluorobenzene (1.0 mL) inacetone (20 mL) was treated with 2,2,2-trifluoroethanol (1.2 mL) andEt₃N (1.2 mL). The reaction mixture was warmed to 45-50° C. for 3 h, thevolatiles were removed in vacuo, and the residue was dissolved in EtOAc(40 mL). The organic layer was washed with water (50 mL) and brine (50mL). The aqueous layers were extracted with EtOAc (2×30 mL). The organiclayers were combined, dried (K₂CO₃), filtered through a pad of Celite,and concentrated to afford orange oil. Purification by silica gelchromatography (hexane:EtOAc, 4:1) to afford 2.1 g (99%) of Compound 572as an orange oil: ¹H NMR (400 MHz, CDCl₃) 8.80 (d, J=2.8, 1H), 8.49 (dd,J=8.3, 2.8, 1H), 7.25 (d, J=8.3, 1H), 4.63 (q, J=7.6, 2H).

2,4-Diaminophenyl(2,2,2-trifluoroethyl)ether (Compound 573, Structure 82of Scheme XVI):

In a 100 mL flask, a solution of Compound 572 (0.85 g) in 1:1 EtOH:EtOAc(40 mL) was treated with 10% Pd/C (0.2 g) and stirred under anatmosphere of hydrogen for 2 h. The reaction mixture was filtered andconcentrated to afford 0.62 g (92%) of Compound 573 as a white solid: ¹HNMR (400 MHz, acetone-d₆) 6.67 (d, J=8.5, 1H), 6.12 (d, J=2.6, 1H), 5.92(dd, J=8.5, 2.6, 1H), 4.39 (q, J=8.9, 2H), 4.28 (br exch s, 2H), 4.17(br exch s, 2H).

7-Amino-6-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-2(1H)-quinolinone(Compound 571, Structure 83 of Scheme XVI):

Compound 573 (0.62 g) was dissolved in toluene (20 mL), treated with4,4,4-trifluoroacetoacetate (0.58 mL), and the reaction mixture washeated to reflux for 1 h. To this solution was added ZnCl₂ (0.26 g) andthe reaction mixture was heated to reflux for 2 h. p-Toluenesulfonicacid hydrate (0.1 g) was added and the reaction mixture maintained areflux for 1 h. The bulk of the volatiles were removed in vacuo and theresidue was poured into 0.5 N NaHSO₄ (20 mL). The reaction mixture wasextracted with EtOAc (3×30 mL). The extracts were washed with water (20mL) and brine (20 mL), combined, dried (MgSO₄), filtered, andconcentrated. The crude material was suspended in 15:1 CH₂Cl₂:MeOH andthe yellow solid collected by filtration to afford 471 mg (43%) ofCompound 571 as a yellow-white solid: R_(f) 0.14 (15:1 CH₂Cl₂:MeOH); ¹HNMR (400 MHz, DMSO-d₆) 11.94 (br s, 1H), 7.01 (s, 1H), 6.66 (s, 1H),6.51 (s, 1H), 6.01 (br exch s, 2H), 4.76 (q, J=8.8, 2H).

EXAMPLE 2947-Isobutylmino-6-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-2(1H-quinolinone(Compound 574, Structure 84 of Scheme XVI, Where R=Isobutyl)

In a 20 mL r.b. flask, a solution of Compound 571 (Structure 83 ofScheme XVI) (39 mg) in AcOH (1 mL) was treated with isobutyraldehdye (16μL) and Na(CN)BH₃ (11 mg). The reaction mixture was stirred overnight,poured into 20% KOH (6 mL), and extracted with EtOAc (3×6 mL). Theextracts were washed with 20% KOH (6 mL) and brine (6 mL); combined,dried (MgSO₄), filtered, and concentrated. Purification by silica gelchromatography (CH₂Cl₂:MeOH, 30:1 to 15:1 gradient) afforded 19 mg (54%)of Compound 574 as a yellow solid: R_(f) 0.32 (15:1 CH₂Cl₂:MeOH); ¹H NMR(400 MHz, acetone-d₆) 10.72 (br exch s, 1H), 7.15 (s, 1H), 6.69 (s, 1H),6.54 (s, 1H), 5.77 (br exch s, 1H), 4.77 (q, J=8.5, 2H), 3.11 (t, J=6.4,2H), 0.99 (d, J=6.7, 6H). The methine proton is obscured by the acetoneheptet.

EXAMPLE 2957-(2-Picolylamino)-6-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-2(1H)-quinolinone(Compound 575, Structure 84 of Scheme XVI, R=2-Picolyl)

In a 20 mL flask, a solution of Compound 293 (Structure 83 of SchemeXVI) (38 mg) in AcOH (1 mL) was treated with 2-pyridinecarboxaldehyde(16 μL) and Na(CN)BH₃ (11 mg). The reaction mixture was stirredovernight, poured into 20% KOH (6 mL), and extracted with EtOAc (3×6mL). The extracts were washed with 20% KOH (6 mL) and brine (6 mL);combined, dried (MgSO₄), filtered, and concentrated. Purification bysilica gel chromatography (CH₂Cl₂:EtOAc:MeOH, 85:10:5) afforded 31 mg(60%) of Compound 295 as a yellow solid: R_(f) 0.18 (CH₂Cl₂:EtOAc:MeOH,85:10:5); ¹H NMR (400 MHz, acetone-d₆) 10.80 (br exch s, 1H), 8.56 (d,J=8.4, 1H), 7.77 (m, 1H), 7.41 (d, J=7.6, 1H), 7.25 (m, 1H), 7.20 (s,1H), 6.72 (br exch s, 1H), 6.60 (s, 1H), 6.55 (s, 1H), 5.77 (br exch s,1H), 4.85 (q, J=8.5, 2H), 4.61 (d, J=5.6, 2H).

EXAMPLE 296 7-Amino-6-methyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 576, Structure 88 of Scheme XVII, R¹=Methyl, R²═R³=H)

This compound was prepared by the following General Procedure XVII(Condensation of 4-alkyl-1,3-phenylenediamine with acetoacetates ortheir corresponding hydrates followed by Knorr reaction mediated byp-toluenesulfonic acid):

To a solution of 4-alkyl-1,3-phenylenediamine (Structure 87 of SchemeXVII) in benzene or toluene (10 mL/mmol) under N₂ was added anacetoacetate derivative (1.2 equiv) and the reaction mixture was heatedat reflux for 4-8 h, then cooled and concentrated under reducedpressure. The crude mixture was then triturated with Et₂O:Hexane (3:1, 4mL/mmol), then redissolved in toluene:EtOH (10:1, 10 mL/mmol) andtreated with p-toluenesulfonic acid. The reaction mixture was thenheated at reflux for 1-2 h. After cooling, the excess solvent wasremoved and the crude product redissolved in EtOAc (100 mL/mmol). Theorganic solution was washed with saturated NaHCO₃ (2×25 mL/mmol), Brine(25 mL/mmol), dried (MgSO₄), filtered, and concentrated under reducedpressure to afford the desired quinolinone as a white solid. If needed,the desired product was further purified by silica gel chromatography asindicated.

Compound 576 was prepared from 2,4-diaminotoluene (1.0 g, 8.2 mmol) in40% yield (0.80 g) as yellow needles: ¹H NMR (400 MHz, DMSO-d₆) 11.00(br s, 1H), 7.21 (s, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 2.10 (s, 3H).

EXAMPLE 297 7-Amino-6-ethyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 577, Structure 88 of Scheme XVII, Where R¹=Ethyl, R²═R³=H)

2-Ethyl-5-nitroaniline (Compound 578, Structure 86 of Scheme XVII, WhereR¹=Ethyl, R²═R³=H):

This compound is prepared according to the following General ProcedureXVIII (nitration of amine):

A solution of an alkylaniline in conc H₂SO₄ (6 mL/mmol) was cooled to−10° C., then treated with a 25% solution of fuming HNO₃ (1.0 equiv)dissolved in H₂SO₄. The rate of addition is adjusted so as to keep thetemperature below −5° C. After complete addition of the HNO₃ solution,the reaction was allowed to stir at −10° C. for 15 min, warmed to roomtemperature, poured over NaOH pellets (0.7 g/mL H₂SO₄) and ice. Theaqueous solution was stirred over ice to dissolve all the NaOH, filteredthen washed with water (2.0 mL/mmol) to afford the desired product as anyellow-orange solid.

Compound 578 was prepared from 2-ethylaniline (200 mg, 1.62 mmol) in 97%yield as a yellow oil: ¹H NMR (400 MHz, CDCl₃) 7.59 (dd, J=8.3, 2.3,1H), 7.50 (d, J=2.2, 1H), 7.17 (d, J=8.3, 1H), 3.90 (bs, 2H), 2.56 (q,J=7.6, 2H), 1.28 (t, J=7.4, 3H).

4-Ethyl-1,3-phenylenediamine (Compound 579, Structure 87 of Scheme XVII,Where R¹=Ethyl, R²═R³=H):

This compound is prepared according to General Procedure III fromCompound 578 (110 mg, 0.66 mmol) in 76% yield. Compound 579 was isolatedas a light brown oil: ¹H NMR (400 MHz, CDCl₃) 6.84 (d, J=8.0, 1H), 6.12(dd, J=8.0, 2.3, 1H), 6.06 (d, J=2.3, 1H), 3.50 (bs, 4H), 2.42 (q,J=7.5, 2H), 1.19 (t, J=7.5, 3H).

7-Amino-6-ethyl-4-trifluoromethyl-2(1H)-quinolinone (Compound 577,Structure 88 of Scheme XVII, Where R¹=Ethyl, R²=R³H):

This compound was prepared according to General Procedure XVII inExample 296 from Compound, 579 (69 mg, 0.50 mmol) andethyl-4,4,4-trifluoroacetoacetate (0.09 mL, 0.62 mmol) and purified byflash chromatography (MeOH/CH₂Cl₂, 1% to 4% gradient), to afford 63 mg(52%) of Compound 577 as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) 11.80(s, 1H), 7.20 (s, 1H), 6.54 (s, 1H), 6.42 (s, 1H), 5.98 (s, 2H), 2.50(m, 2H), 1.14 (t, J=7.4, 3H).

EXAMPLE 298 7-Amino-6-propyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 580, Structure 88 of Scheme XVII, Where R¹=Propyl, R²═R³=H)

This compound is prepared in a similar fashion as that described inExamples 297 and 1, General Procedure XVIII, and III but using2-propylaniline (Structure 85 of Scheme XVII, where R¹=propyl, R²═R³=H)(0.20 mL, 1.42 mmol) in place of 2-ethylaniline.

Data for 2-propyl-5-nitroaniline (Structure 86 of Scheme XVII, whereR¹=propyl, R²═R³=H): ¹H NMR (400 MHz, CDCl₃) 7.56 (dd, J=8.2, 2.3, 1H),7.50 (d, J=2.3, 1H), 7.14 (d, J=8.3, 1H), 3.90 (bs, 2H), 2.52 (t, J=7.8,2H), 1.66 (sex, J=7.5, 2H), 1.01 (t, J=7.3, 3H).

Data for 4-propyl-1,3-phenylenediamine (Structure 87 of Scheme XVII,where R¹=propyl, R²=R³H): ¹H NMR (400 MHz, CDCl₃) 6.81 (d, J=8.1, 1H),6.09 (dd, J=8.2, 2.3, 1H), 6.02 (d, J=2.3, 1H), 3.50 (bs, 4H), 2.40 (t,J=7.8, 2H), 1.58 (sex, J=7.5, 2H), 0.97 (t, J=7.3, 3H).

Data for Compound 580 (Structure 88 of Scheme XVII, where R¹=propyl,R²═R³=H): ¹H NMR (400 MHz, DMSO-d₆) 11.78 (s, 1H), 7.17 (s, 1H), 6.52(s, 1H), 6.41 (s, 1H), 5.96 (s, 2H), 2.45 (t, J=7.6, 2H), 1.52 (m, 2H),0.92 (t, J=7.3, 3H).

EXAMPLE 299 7-Amino-6-sec-butyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 581, Structure 88 of Scheme XVII, Where R¹=sec-Butyl, R²═R³=H)

This compound is prepared in a similar fashion as that described inExamples 297 and 1, General Procedure XVIII and III but using2-s-butyl-aniline (Structure 85 of Scheme XVI, where R¹=sec-butyl,R²═R³=H) (0.20 mL, 1.28 mmol) in place of 2-ethylaniline.

Data for 2-sec-butyl-5-nitroaniline (Structure 86 of Scheme XVII, whereR¹=sec-butyl, R²═R³=H): ¹H NMR (400 MHz, CDCl₃) 7.60 (dd, J=8.5, 2.3,1H), 7.50 (d, J=2.4, 1H), 7.19 (d, J=8.5, 1H), 3.92 (bs, 2H), 2.67 (sex,J=6.9, 1H), 1.66 (m, 2H), 1.25 (d, J=6.8, 3H), 0.91 (t, J=7.3, 3H).

Data for 4-sec-butyl-1,3-phenylenediamine (Structure 87 of Scheme XVII,where R¹=sec-butyl, R²═R³=H): ¹H NMR (400 MHz, CDCl₃) 6.86 (d, J=8.3,1H), 6.14 (dd, J=8.2, 2.4, 1H), 6.08 (d, J=2.3, 1H), 3.60 (bs, 4H), 2.53(sex, J=6.9, 1H), 1.52 (m, 2H), 1.15 (d, J=6.7, 3H), 0.86 (t, J=7.2,3H).

Data for Compound 581 (Structure 88 of Scheme XVII, where R¹=sec-butyl,R²═R³=H): ¹H NMR (400 MHz, DMSO-d₆) 11.78 (s, 1H), 7.19 (s, 1H), 6.53(s, 1H), 6.42 (s, 1H), 5.99 (s, 2H), 2.80 (m, 1H), 1.56-1.48 (m, 2H),1.0 (t, J=3.8, 3H), 0.83 (t, J=7.3, 3H).

EXAMPLE 300 7-Amino-6-cyclohexyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 582, Structure 88 of Scheme XVII, Where R¹=Cyclohexyl,R²═R³=H)

4-Cyclohexyl-3-nitroaniline (Compound 583, Structure 91 of Scheme XVII):

This compound is prepared according to General Procedure XVIII inExample 297 from 4-cyclohexyl-aniline (285 mg, 1.62 mmol) and HNO₃ (90mg, 1.62 mmol) in 94% yield. Compound 583 was isolated as a white solid:¹H NMR (400 MHz, CDCl₃) 7.20 (d, J=8.4, 1H), 6.97 (d, J=2.5, 1H), 6.81(dd, J=8.5, 2.5, 1H), 3.78 (bs, 2H), 2.85 (m, 1H), 1.83 (m, 4H), 1.75(m, 1H), 1.36 (m, 4H), 1.23 (m, 1H).

4-Cyclohexyl-1,3-phenylenediamine (Compound 584, Structure 87 of SchemeXVII, Where R¹=Cyclohexyl, R²═R³=H):

This compound is prepared according to General Procedure III in Example1 from Compound 583 (353 mg, 1.60 mmol) and purified by flashchromatography (MeOH/CH₂Cl₂, 0% to 2% gradient). Compound 582 wasisolated in 96% yield as a light brown oil: ¹H NMR (400 MHz, CDCl₃) 6.88(d, J=8.1, 1H), 6.15 (dd, J=8.1, 2.3, 1H), 6.06 (d, J=2.4, 1H), 3.48(bs, 4H), 2.35 (m, 1H), 1.84 (m, 4H), 1.75 (m, 1H), 1.37 (m, 4H), 1.25(m, 1H).

7-Amino-6-cyclohexyl-1,2-dihydro-4-trifluoromethyl-2(1H)-quinolinone(Compound 582, Structure 88 of Scheme XVII, Where R¹=Cyclohexyl,R²═R³=H):

This compound was prepared according to General Procedure XVII inExample 296 from Compound 584 (69 mg, 0.50 mmol) and ethyl4,4,4-trifluoroacetoacetate (0.09 mL, 0.62 mmol) and purified by flashchromatography (MeOH/CH₂Cl₂, 1% to 4% gradient). Compound 582 wasisolated in 52% yield as a white solid: ¹H NMR (400 MHz, DMSO-d₆) 11.78(s, 1H), 7.21 (s, 1H), 6.53 (s, 1H), 6.41 (s, 1H), 5.99 (s, 2H), 2.60(t, J=11.6, 1H), 1.82-1.69 (m, 5H), 1.50-1.41 (m, 2H), 1.29-1.21 (m,3H).

EXAMPLE 3016-Ethyl-7-(2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 585, Structure 89 of Scheme XVII, Where R¹=Ethyl, R²=H,R³=2,2,2-Trifluoroethyl)

This compound is prepared in a similar fashion as that described inExample 9, General Procedure VI but using Compound 577 (Structure 88 ofScheme XVII, where R¹=ethyl, R²=R³H) and TFA in place of Compound 200and 2,2-difluoroacetic acid. Compound 585 was isolated as a white solid:¹H NMR (400 MHz, CD₃CN) 9.72 (bs, 1H), 7.42 (s, 1H), 6.63 (s, 1H), 6.60(s, 1H), 5.30 (bs, 1H), 3.96 (m, 2H), 2.58 (q, J=7.5, 2H), 1.20 (t,J=7.7, 3H).

EXAMPLE 302 6-Ethyl-7-methylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 586, Structure 89 of Scheme XVII, Where R¹=Ethyl, R²=H,R²=Methyl)

This compound is prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 577 (Structure 88 ofScheme XVII, where R¹=ethyl, R²═R³=H) and paraformaldehyde in place ofCompound 200 and propionaldehyde. Compound 586 was isolated as a whitesolid: ¹H NMR (400 MHz, CD₃CN) 10.85 (bs, 1H), 7.54 (s, 1H), 7.13 (s,1H), 6.73 (s, 1H), 2.76 (q, J=7.5, 2H), 1.26 (t, J=7.4, 3H).

EXAMPLE 303 6-Ethyl-7-dimethylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 587, Structure 89 of Scheme XVII, Where R¹=Ethyl,R²═R²=Methyl)

This compound is prepared in a similar fashion as that described inExample 15, General Procedure VIII but using Compound 577 (Structure 88of Scheme XVII, where R¹=ethyl, R²═R³=H) a in place of Compound 200.Compound 587 was isolated as a white solid: ¹H NMR (400 MHz, CD₃CN)11.66 (bs, 1H), 7.60 (s, 1H), 6.90 (s, 1H), 6.88 (s, 1H), 2.83 (s, 6H),2.76 (q, J=7.5, 2H), 1.29 (t, J=7.5, 3H).

EXAMPLE 304 6-Isobutyl-7-methylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 588Structure 89 of Scheme XVII, Where R¹=Isobutyl, R²=H,R²=Methyl)

This compound is prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 581 (Structure 88 ofScheme XVII, where R¹=isobutyl, R²═R³=H) and paraformaldehyde in placeof Compound 200 and propionaldehyde. Compound 588 was isolated as awhite solid: ¹H NMR (400 MHz, CDCl₃) 11.36 (bs, 1H), 7.43 (d, J=1.8,1H), 6.74 (s, 1H), 6.40 (s, 1H), 4.39 (bm, 1H), 3.00 (d, J=5.0, 3H),2.58 (dt, J=6.8, 1H), 1.76-1.68 (m, 1H), 1.64-1.57 (m, 1H), 1.25 (d,J=2.8, 3H), 0.92 (t, J=7.6, 3H).

EXAMPLE 305 7-(1-Morpholino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 589, Structure 88 of Scheme XVII, Where R¹=H,NR²R³=Morpholino)

1-(3-Nitrophenyl)morpholine (Compound 590, Structure 86 of Scheme XVII,where R¹=H, NR²R³=Morpholino):

In a 100 mL flask, a solution of 1-phenylmorpholine (Structure 85 ofScheme XVII, where R¹=H, NR²R³=morpholino) (0.63 g) in concentratedsulfuric acid (5 mL) was cooled to −5° C. To this solution, 90% fumingnitric acid (0.17 mL) was added dropwise via syringe over a 3-minuteperiod. The reaction mixture was stirred for 5 min, poured onto ice (50g), and neutralized by portionwise addition of K₂CO₃ (˜5 g). Thereaction mixture was poured into water (20 mL) and extracted with CH₂Cl₂(3×50 mL). The extracts were washed with saturated NaHCO₃ (50 mL),combined, dried (MgSO₄), filtered through a pad of Celite, andconcentrated to afford 0.78 g of an orange solid which was purified bysilica gel chromatography (hexane:EtOAc, 8:1) to afford 0.33 g (41%) ofCompound 590 as orange crystals: ¹H NMR (400 MHz, CDCl₃) 7.71 (m, 2H),7.40 (t, J=8.1, 1H), 7.18 (dd, J=8.5, 2.4, 1H), 3.89 (t, J=4.8, 4H),3.25 (t, J=4.8, 4H).

7-(1-Morpholino)-4-trifluoromethyl-2(1H)-quinolinone (Compound 589,Structure 88 of Scheme XVII, Where R¹=H, NR²R³=Morpholino):

In a 100 mL flask, a solution of Compound 590 (0.33 g) in EtOAc (12 mL)was treated with 10% Pd/C (50 mg) and stirred under an atmosphere of H₂for 14 h. The reaction mixture was filtered and concentrated to afford1-(3-aminophenyl)morpholine (Compound 591, Structure 87 of Scheme XVII,where R¹=H, NR²R³=morpholino) as a white solid, which was used withoutfurther purification. Compound 591 was dissolved in EtOH (10 mL),treated with ethyl 4,4,4-trifluoroacetoacetate (0.27 mL), and stirred atroom temperature for 10 min. To this solution was added ZnCl₂ (0.26 g)and the reaction mixture was heated to reflux for 12 h. The bulk of thevolatiles were removed in vacuo and the residue was poured into 0.5 NNaHSO₄ (20 mL). The reaction mixture was extracted with EtOAc (3×30 mL).The extracts were washed with water (20 mL) and brine (20 mL), combined,dried (MgSO₄), filtered, and concentrated. Purification by silica gelchromatography (CH₂Cl₂:MeOH, 60:1 to 15:1 gradient) afforded 22 mg (5%)of Compound 589 as a white solid: R_(f) 0.19 (15:1 CH₂Cl₂:MeOH); ¹H NMR(400 MHz, acetone-d₆) 11.95 (br s, 1H), 7.50 (d, J=7.8, 1H), 7.02 (d,J=7.8, 1H), 6.77 (s, 1H), 6.63 (s, 1H), 3.75 (t, J=4.8, 4H), 3.25 (t,J=4.8, 4H).

EXAMPLE 306 5-Amino-7-chloro-4-trifluoromethyl-2(1H)-quinolinone(Compound 592, Structure 94 of Scheme XVIII, Where R¹=H, R²=Chlrorine)

To a solution of 5-chloro-3-phenylenediamine (Structure 92 of SchemeXVIII, where R¹=H, R²=chlorine) (2.5 g, 17.63 mmol) and EtOH (10 mL) wasadded ethyl 4,4,4-trifluoroacetoacetate (2.7 mL, 17.9 mmol). The darkreaction mixture was heated to reflux under nitrogen. After 15 hrs, thereaction mixture was filtered to afford 3.0 g (61%) of5-Amino-7-chloro-4-hydroxy-4-trifluoromethyl-3,4-dihydro-2-(1H)-quinolinone(Compound 593, Structure 93 of Scheme XVIII, where R¹=H, R²=chlorine) asa gray-brown solid: ¹H NMR (400 MHz, DMSO-d₆) 10.12 (brs, 1H), 7.44 (s,1H), 6.33 (d, J=2.1, 1H), 6.11 (d, J=2.1, 1H), 5.86 (s, 2H), 3.05 (d,J=16.4, 1H), 2.69 (d, J=16.4, 1H). The filtrate was purified bychromatography (5-50% EtOAc/hex) to afford 100 mg of Compound 592 as ayellow solid: ¹H NMR (400 MHz, DMSO-d₆) 11.50 (brs, 1H), 6.82 (s, 1H),6.70 (d, J=1.8, 1H), 6.67 (d, J=1.8, 1H), 5.68 (s, 2H).

Compound 593 was converted to Compound 592 by the treatment with anacid.

EXAMPLE 307 5-Propylamino-7-chloro-4-trifluoromethyl-2(1H)-quinolinone(Compound 594, Structure 96 of Scheme XVIII, Where R=Propyl, R¹=H,R²=Chlrorine)

This compound was prepared in a similar fashion as that described inExample 2, General Procedure IV but using Compound 592 (Structure 94 ofScheme XVIII, where R¹=H, R²=chlorine) (50 mg, 0.19 mmol) in place ofCompound 200. Compound 594 was isolated in 90% yield as a yellow solid:¹H NMR (400 MHz, CD₃OD) 6.90 (s, 1H), 6.65 (s, 1H), 4.99 (brs, 1H), 3.10(m, 2H), 1.62 (q, J=7.4, 2H), 1.05 (t, J=7.4, 3H).

EXAMPLE 308 7-Chloro-5-hydroxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 595, Structure 95 of Scheme XVIII, Where R¹=H, R²=Chlrorine)

A mixture of Compound 593 (Structure 93 of Scheme XVIII, where R¹=H,R²=chlorine) (100 mg, 0.36 mmol), water (5 mL), concn. H₂SO₄ (4 mL) andice (6 g) was cooled to 0° C. An aqueous solution (1 mL) of sodiumnitrite (28 mg, 0.40 mmol) was added dropwise with stirring. The mixturewas cautiously poured into 15 mL of boiling (140° C.) 10 M H₂SO₄. Theboiling was continued for 10 min. and the mixture was diluted with waterand cooled to room temperature to give a yellow/orange precipitate whichwas filtered and washed with water then dissolved in acetone andconcentrated in vacuo to afford 80 mg (84%) of Compound 595 as a yellowsolid: ¹H NMR (400 MHz, acetone-d₆) 11.10 (brs, 1H), 10.25 (brs, 1H),7.05 (d, J=1.8, 1H), 6.89 (s, 1H), 6.80 (d, J=1.8, 1H).

EXAMPLE 3095-Amino-6-bromo-3,4-dihydro-4-hydroxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 596, Structure 93 of Scheme XVIII, Where R¹=Bromine, R²=H)

4-Bromophenylenediamine (Compound 597, Structure 92 of Scheme XVIII,Where R¹=Bromine, R²=H):

A suspension of 2-bromo-5-nitroaniline (10 g, 46 mmol), zinc dust (15 g,0.23 mol), and calcium chloride dihydrate (20 g, 0.14 mol) in 140 mL 95%EtOH/water was heated at reflux for 12 h. The mixture was filteredthrough Celite, washed with hot EtOAc and concentrated to a tan solid.Flash chromatography (50% EtOAc/hexanes) afforded 5.8 g (67%) ofCompound 597: ¹H NMR (400 MHz, CDCl₃) 7.13 (d, 1H, J=8.5), 6.12 (d, 1H,J=2.6), 6.01 (dd, 1H, J=8.5, 2.6), 3.95 (broad s, 2H), 3.56 (broad s,2H).

5-Amino-6-bromo-3,4-dihydro-4-hydroxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 596, Structure 93 of Scheme XVIII, Where R¹=Bromine, R²=H):

To a solution of Compound 597 (5.7 g, 30 mmol) in 100 mL toluene wasadded ethyl trifluoroacetoacetate (4.9 mL, 34 mmol, 1.1 eq) dropwise.The solution was heated at reflux for 18 h. The solvent was allowed tocool to room temperature, then placed in a refrigerator (0° C.). Thesolid was filtered and rinsed with cold toluene. Flash chromatography(1:1 EtOAc:dichloromethane) afforded 3.6 g (37%) of Compound 596 as atan solid: ¹H NMR (400 MHz, acetone-d₆) 9.31 (broad s, 1H), 7.37 (d, 1H,J=8.5), 6.73 (s, 1H), 6.28 (d, 1H, J=8.5), 5.83 (broad s, 2H), 3.16 (d,AB, 1H, J=16.9), 2.97 (d, AB, 1H, J=16.9).

EXAMPLE 310 6-Bromo-5-chloro-4-trifluoromethyl-2(1H)-quinolinone(Compound 598, Structure 98 of Scheme XVIII, Where R¹=Bromine, R²=H)

6-Bromo-5-chloro-3,4-dihydro-4-hydroxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 599, Structure 97 of Scheme XVIII, Where R¹=Bromine, R²=H):

In a dry flask, to a solution of CuCl₂ (2.5 g, 18 mmol, 2 eq) in 60 mLanhydrous acetonitrile was added t-butyl nitrite (2.1 mL, 18 mmol, 1.9eq). The solution turned black. A solution of the aniline (3.0 g, 9.3mmol) in 150 mL was added via cannula. The mixture was stirred at rt for3 h, then partitioned with EtOAc (200 mL) and water (200 mL). The waterlayer was extracted with EtOAc (200 mL), washed with sat'd NaHCO₃ (100mL), then brine (100 mL), dried (MgSO₄), filtered and concentrated. Thecrude material was purified by flash chromatography (95:5 hexanes:EtOAc,gradient to 50:50 hexanes:EtOAc) to afford 2.5 g (79%) of Compound 599as an off-white solid: ¹H NMR (400 MHz, CDCl₃) 9.74 (broad s, 1H), 7.66(d, 1H, J=8.5), 6.82 (d, 1H, J=8.5), 5.08 (s, 1H), 3.19 (d, AB, 1H,J=17.2), 3.05 (d, AB, 1H, J=17.2).

6-Bromo-5-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 598,Structure 98 of Scheme XVIII, Where R¹=Bromine, R²=H):

A solution of Compound 599 (2.5 g, 7.3 mmol) in 22 mL conc. H₂SO₄ washeated at 90° C. for 1 h, whereupon TLC analysis (1:1 EtOAc:hexanes)showed complete consumption of starting material. The reaction waspoured over ice, and a white precipitate formed. The solid was filteredand washed with hexanes. The solid was dissolved in hot EtOAc andfiltered through Celite to afford 2.2 g (92%) of an off-white solid. ¹HNMR (400 MHz, acetone-d₆) 11.4 (broad s, 1H), 7.99 (d, 1H, J=9.0), 7.49(d, 1H, J=9.0), 7.22 (s, 1H).

EXAMPLE 3116-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-methoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 600, Structure 100 of Scheme XVIII, Where R=Methoxy,R¹═R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from6-amino-5-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 601,Structure 99 of Scheme XVIII, where R=methoxy) and trifluoroacetic acid.Compound 600 was isolated as yellow solid. ¹H NMR (CDCl₃, 500 MHz)12.00-12.20 (bs, 1H), 7.45 (d, J=8.8, 1H), 7.22 (d, J=2.9, 1H), 7.20 (s,1H), 4.02 (q, J=8.8, 4H), 3.88 (s, 3H).

EXAMPLE 3126-(N-2,2,2-Trifluoroethyl)amino-5-propyloxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 602, Structure 100 of Scheme XVIII, Where R=Propyloxy, R¹=H,R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from6-amino-5-propyloxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 603,Structure 99 of Scheme XVIII, where R=propyloxy) and trifluoroaceticacid. Compound 602 was isolated as yellow solid. ¹H NMR (CDCl₃) 10.56(bs, 1H), 7.18 (s, 1H), 4.14 (d, J=9.6, 1H), 7.11 (d, J=9.6, 1H), 4.45(t, J=6.6, 1H), 3.83 (quin, J=7.4, 2H), 3.74 (t, J=6.6, 2H), 1.86 (q,J=7.3, 2H), 1.07 (t, J=7.4, 3H).

EXAMPLE 3136-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-propyloxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 604, Structure 100 of Scheme XVIII, Where R=Propyloxy,R¹═R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 603 (Structure 99 ofScheme XVIII, where R=propyloxy) and trifluoroacetic acid. Compound 604was isolated as yellow solid. ¹H NMR (CDCl₃) 10.75 (bs, 1H), 7.43 (d,J=9.0, 1H), 7.19 (s, 1H), 7.17 (d, J=9.0, 1H), 4.03 (q, J=8.9, 4H), 3.93(t, J=7.1, 2H), 1.83 (q, J=7.3, 2H), 1.01 (t, J=7.4, 3H).

EXAMPLE 3146-(N-2,2,2-Trifluoroethyl)amino-5-ethoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 605, Structure 100 of Scheme XVIII, Where R=Ethoxy, R¹=H,R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from6-amino-5-ethoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 606,Structure 99 of Scheme XVIII, where R=ethoxy) and trifluoroacetic acid.Compound 605 was isolated as yellow solid. ¹H NMR (CDCl₃) 10.65 (bs,1H), 7.17 (s, 1H), 7.11 (s, 1H), 4.44 (t, 7.2, 1H), 3.86-3.81 (m, 4H),1.44 (t, J=6.9, 3H).

EXAMPLE 3156-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-ethoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 607, Structure 100 of Scheme XVIII, Where R=Ethoxy,R¹═R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 606 (Structure 99 ofScheme XVIII, where R=ethoxy) and trifluoroacetic acid. Compound 607 wasisolated as yellow solid. ¹H NMR (CDCl₃) 11.05 (bs, 1H), 7.44 (s, 1H),7.20 (s, 2H), 4.05 (m, 6H), 1.39 (t, J=6.9, 3H).

EXAMPLE 3166-(N-2,2,2-Trifluoroethyl)amino-5-(3,3,3-trifluoropropyloxy)-4-trifluoromethyl-2(1H)-quinolinone(Compound 608, Structure 100 of Scheme XVIII, WhereR=3,3,3-Trifluoropropyloxy, R¹=H, R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from6-amino-5-(3,3,3-trifluoropropyloxy)-4-trifluoromethyl-2(1H)-quinolinone(Compound 609, Structure 99 of Scheme XVIII, whereR=3,3,3-trifluoropropyloxy) and trifluoroacetic acid. Compound 608 wasisolated as yellow solid. ¹H NMR (CDCl₃) 11.15 (bs, 1H), 7.92 (d, J=6.7,1H), 7.72 (d, J=6.7, 1H), 7.59 (m, 2H), 4.23 (m, 2H), 1.67 (m, 2H), 1.41(m, 2H).

EXAMPLE 3176-(N-2,2,2-Trifluoroethyl)amino-5-chloro-4-trifluoromethyl-2(1H)-quinolinone(Compound 610, Structure 100 of Scheme XVIII, Where R=Chloro, R¹=H,R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from6-amino-5-chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 611,Structure 99 of Scheme XVIII, where R=chloro) and trifluoroacetic acid.Compound 610 was isolated as yellow solid. ¹H NMR (CDCl₃) 11.15 (bs,1H), 7.38 (d, J=9.1, 1H), 7.33 (s, 1H), 7.17 (d, J=9.1, 1H), 5.07 (t,J=8.3, 1H), 3.92 (quin, J=8.5, 2H).

EXAMPLE 3186-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-chloro-4-trifluoromethyl-2(1H)-quinolinone(Compound 612, Structure 100 of Scheme XVIII, Where R=Chloro,R¹═R²=2,2,2-Trifluoroethyl)

This compound was prepared in a similar fashion as that described inExample 9, General Procedure VI from Compound 611 (Structure 99 ofScheme XVIII, where R=chloro) and trifluoroacetic acid. Compound 612 wasisolated as yellow solid. ¹H NMR (CDCl₃) 10.62 (bs, 1H), 7.6 (d, J=8.7,1H), 7.39 (d, J=8.8, 1H), 7.34 (s, 1H), 3.83 (q, J=8.6, 4H).

EXAMPLE 319 6-Fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound 613,Structure 102 of Scheme XIX, Where R¹═R³═R⁴=H, R²=Fluorine)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 4-fluoroaniline (Structure 101of Scheme XIX, where R³═R⁴=H, R²=fluorine) in place of Compound 200.Compound 613 was isolated as a white solid: ¹H NMR (400 MHz, acetone-d₆)10.87 (s, 1H), 7.58-7.48 (m, 2H), 7.43 (d, J=9.7, 1H), 7.01 (s, 1H).

EXAMPLE 320 6-Chloro-4-trifluoromethyl-2(1H)-quinolinone (Compound 614,Structure 102 of Scheme XIX, Where R¹═R³═R⁴=H, R²=Chlorine)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 4-chloroaniline (Structure 101of Scheme XIX, where R²=fluorine, R³═R⁴=H) in place of Compound 200.Compound 614 was isolated as a white solid: ¹H NMR (400 MHz,acetone-d₆+drop of DMSO-d₆) 10.90 (s, 1H), 7.68-7.60 (m, 2H), 7.53 (d,J=9.0, 1H), 7.01 (s, 1H).

EXAMPLE 321 6-Isopropyl-4-trifluoromethyl-2(1H)-quinolinone (Compound615, Structure 102 of Scheme XIX, Where R¹═R³═R⁴=H, R²=Isopropyl)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 4-isopropylaniline (Structure101 of Scheme XIX, where R²=isopropyl, R³═R⁴=H) in place of Compound200. Compound 615 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃)10.60 (s, 1H), 7.64 (s, 1H), 7.50 (d, J=8.1, 1H), 7.27 (d, J=8.1, 1H),7.06 (s, 1H), 5.45 (q, J=5.6, 1H), 1.43 (d, J=5.6, 6H).

EXAMPLE 322 6-Cyclohexyl-4-trifluoromethyl-2(1H)-quinolinone (Compound616, Structure 102 of Scheme XIX, Where R¹═R³═R⁴=H, R²=Cyclohexyl)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 4-cyclohexylaniline (Structure101 of Scheme XIX, where R²=cyclohexyl, R³═R⁴=H) in place of Compound200. Compound 616 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃)11.75 (bs, 1H), 7.62 (s, 1H), 7.49 (dd, J=8.4, 1.5, 1H), 7.42 (d, J=8.7,1H), 7.08 (s, 1H), 2.60 (bt, 1H), 1.90 (m, 4H), 1.78 (m, 1H), 1.43 (m,4H), 1.26 (m, 1H).

EXAMPLE 323 6-(1-trans-Propenyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 617, Structure 102 of Scheme XIX, Where R¹═R³═R⁴=H,R²=1-Propenyl)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 4-(1-trans-propenyl)aniline(Structure 101 of Scheme XIX, where R²=1-trans-propenyl, R³═R⁴=H) inplace of Compound 200. Compound 617 was isolated as a white solid: ¹HNMR (400 MHz, acetone-d₆) 11.60 (s, 1H), 7.76 (dd, J=8.6, 1.6, 1H) 7.65(s, 1H), 7.48 (d, J=8.6, 1H), 6.93 (s, 1H), 6.54 (d, J=15.8, 1H),6.38-6.32 (m, 1H), 1.88 (dd, J=6.4, 1.3, 3H).

EXAMPLE 324 6-Cyclohexyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone(Compound 618, Structure 102 of Scheme XIX, Where R¹=Fluorine,R²=Cyclohexyl R³═R⁴=H)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 4-cyclohexylaniline (Structure101 of Scheme XIX, where R²=cyclohexyl, R³═R⁴=H) and ethyl2,4,4,4-tetrafluoroacetoacetate in place of Compound 200 and4,4,4-trifluoroacetoacetate. Compound 618 was isolated as a white solid:¹H NMR (400 MHz, DMSO-d₆) 12.48 (bs, 1H), 7.49 (m, 2H), 77.38 (d, J=7.6,1H), 2.59 (m, 1H), 1.81 (m, 4H), 1.70 (m, 2H), 1.40 (m, 4H).

EXAMPLE 325 7-Fluoro-6-methyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 619, Structure 102 of Scheme XIX, Where R¹═R³=H, R²=Methyl,R⁴=Fluoro)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 3-fluoro-4-methylaniline(Structure 101 of Scheme XIX, where R³=H, R²=methyl, R⁴=fluoro) and4,4,4-trifluoroacetoacetate in place of Compound 200. Compound 619 wasisolated as a white solid: ¹H NMR (400 MHz, acetone-d₆) 11.22 (s, 1H),7.67 (d, J=7.3, 1H), 7.20 (d, J=10.6, 1H), 6.86 (s, 1H), 2.35 (d, J=1.4,3H).

EXAMPLE 326 7-Difluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound620, Structure 102 of Scheme XIX, Where R¹═R²=H, R³═R⁴=Fluoro)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 3,5-difluoroaniline (Structure101 of Scheme XIX, where R²=H, R³═R⁴=fluoro) and4,4,4-trifluoroacetoacetate in place of Compound 200. Compound 620 wasisolated as a white solid: ¹H NMR (400 MHz, acetone-d₆) 11.50 (s, 1H),7.15 (dd, J=8.6, 2.5, 1H), 7.13-7.01 (m, 2H).

EXAMPLE 327 6-Methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 621,Structure 102 of Scheme XIX, Where R¹═R³═R⁴=H, R²=Methoxy)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I but using 4-methoxyaniline (Structure 101of Scheme XIX, where R²=methoxy, R³═R⁴=H) and4,4,4-trifluoroacetoacetate in place of Compound 200. Compound 621 wasisolated as a white solid: ¹H NMR (400 MHz, acetone-d₆) 7.50 (d, J=9.0,1H), 7.33 (dd, J=9.0 and 2.5, 1H), 7.19 (d, J=2.5, 1H), 6.95 (s, 1H),3.88 (s, 3H).

EXAMPLE 328 6-Benzyloxy-4-trifluoromethyl-2(1H)-quinolinone (Compound623, Structure 104 of Scheme XIX, Where R⁵=Benzyl)

6-Hydroxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 622, Structure103 of Scheme XIX):

To a solution of Compound 621 (Structure 102 of Scheme XIX, whereR¹═R═R⁴=H, R²=methoxy) (0.20 g, 0.82 mmol) in CH₂Cl₂ was added BBr₃ andthe reaction mixture was allowed to stir at rt overnight. The reactionwas quenched with H₂SO₄ (1 M aqueous), extracted with EtOAc and washedwith NaHCO₃ (sat. aqueous). Recrystallization afforded Compound 622(0.17 g, 88%) as a yellow solid: ¹H NMR (400 MHz, acetone-d₆) 1.10 (bs,1H), 8.75 (s, 1H), 7.43 (d, J=8.7, 1H), 7.30-7.18 (m, 2H), 6.93 (s, 1H).

6-Benzyloxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 623, Structure103 of Scheme XIX, where R⁵=Benzyl):

A mixture of Compound 622, benzyl bromide (1 equiv) and Na₂CO₃ inacetone was stirred at rt overnight. Standard procedure affordedCompound 623 as a white solid: ¹H NMR (400 MHz, acetone-d₆) 11.36 (s,1H), 7.52-7.47 (m, 4H), 7.42-7.22 (m, 4H), 7.27 (s, 1H), 5.21 (s, 2H).

EXAMPLE 329 6-(3-Pentyloxy)-4-trifluoromethyl-2(1H)-quinolinone(Compound 624, Structure 104 of Scheme XIX, Where R⁵=3-Pentyl)

A mixture of Compound 622 (Structure 103 of Scheme XVIII),3-bromopentane and sodium hydride in DMF was heated at 130° C. for 2 h.The reaction was quenched with water and extracted with EtOAc. Removalof solvent followed by chromatography provided Compound 624 as a paleyellow solid: ¹H NMR (400 MHz, acetone-d₆) 11.60 (s, 1H), 7.48 (d,J=9.0, 1H), 7.34 (dd, J=9.0, 2.5, 1H), 7.21 (s, 1H), 6.97 (s, 1H), 6.94(s, 1H), 4.26-4.23 (m, 1H), 1.74-1.67 (m, 4H), 0.97 (t, J=7.4, 6H).

EXAMPLE 3306-(1-Hydroxy-3,3,5,5-tetramethyl)cyclohexyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 625, Structure 105 of Scheme XX, Where R═R¹═R²═R⁵═R⁶=H,R³═R⁴=Methyl, n=1, Z=—CH₂CMe₂—)

This Compound was Prepared by the Following General Procedure XIX(Alkylation of an Arylbromide by a Ketone):

A solution of an arylbromide in dry THF (0.1-0.5 M) is cooled to −70° C.under a N₂ atmosphere. The aryl bromide is then treated, if needed foramide deprotonation, with n-BuLi (1.2 equiv) and stirred at −70° C. for15 min before the addition of n-BuLi (1.2 equiv), the reaction mixturewas allowed to stir an additional 20 min at −70° C., warmed to −30° C.,where the dianion is then quenched with a ketone (2.0 equiv). Thereaction mixture is then warmed to room temperature overnight, dilutedwith water and extracted with EtOAc (3×20 mL/mmol). The combined organicextracts were then washed with Brine (20 mL/mmol), dried (MgSO₄),filtered and concentrated. Purification by trituration (EtOAc/hexane,20%) or recrystallization (MeOH) afforded the desired alcohol.

Compound 625 was prepared from Compound 308 (Structure 16a of Scheme XX,where R═R¹=H) as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.99 (s, 1H),7.73 (d, J=8.8, 1H), 7.37 (d, J=8.8, 1H), 7.08 (s, 1H), 2.13 (s, 1H),1.61 (m, 4H), 1.34 (s, 6H), 1.26 (m, 2H), 0.97 (s, 6H).

EXAMPLE 3316-(3,3,5,5-Tetramethyl)cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 626, Structure 106 of Scheme XX, Where R═R¹═R²═R⁵═R⁶=H,R³═R⁴=Methyl, n=1, Z=—CH₂CMe₂—)

This compound was prepared by the following General Procedure XX(Dehydration of an alcohol):

A solution of the benzylic alcohol, such as Compound 625 (Structure 105of Scheme XX, where R═R¹═R²═R⁵═R⁶ 32 H, R³═R⁴=Methyl, n=1, Z=—CH₂CMe₂—),in CH₂Cl₂ (0.1M) is treated with trifluoroacetic acid (excess) or TsOHand stirred for 2 h at room temperature. The reaction mixture is thenpoured into cool saturated NaHCO₃ solution and the pH adjusted to pH 7.The reaction solution is then partitioned and the aqueous layer isextracted with CH₂Cl₂ (3×15 mL/mmol). The combined organic layers arethen washed with water (10 mL/mmol), Brine (10 mL/mmol), dried (MgSO₄),filtered and concentrated to give crude olefin product. Purification byrecrystallization (MeOH/EtOAc) gives pure olefin product in good yield.

Compound 626 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.74(s, 1H), 7.67 (d, J=8.0, 1H), 7.42 (d, J=8.0, 1H), 7.11 (s, 1H), 5.83(s, 1H), 2.23 (s, 2H), 1.44 (s, 2H), 1.12 (s, 6H), 1.06 (s, 6H).

EXAMPLE 3326-(5,5-Dimethycyclopentenyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 627, Structure 106 of Scheme XX, Where R═R¹═R²═R³═R⁴=H,R⁵═R⁶=Methyl, n=1, Z=Methylene)

This compound was prepared in a similar fashion as that described inExamples 330 and 331, General Procedures XIX and XX but using2,2-dimethylcyclopentanone in place of 3,3,5,5-tetramethylcyclohexanone.Compound 627 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.80(s, 1H), 7.60 (d, J=8.0, 1H), 7.39 (d, J=8.0, 1H), 7.11 (s, 1H), 5.85(t, J=4.0, 1H), 2.41 (td, J=4.0, J=8.0, 2H), 1.90 (t, J=8.0, 2H), 1.23(s, 6H).

EXAMPLE 333 (±)-6-(22-Dimethycyclopentyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound 628,Structure 107 of Scheme XX, Where R═R¹═R²═R³═R⁴=H, R⁵═R⁶=Methyl, n=1,Z=Methylene)

This compound was prepared in a similar fashion as that described inExample 1 General Procedure III from Compound 627 (Structure 106 ofScheme XX, where R═R¹═R²═R³═R⁴=H, R⁵═R⁶=methyl, n=1, Z=methylene).Compound 628 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃)11.25 (br s, 1H), 7.62 (s, 1H), 7.45 (d, J=8.0, 1H), 7.30 (d, J=8.0,1H), 7.07 (s, 1H), 2.79 (t, J=8.0, 2H), 2.06 (m, 2H), 1.86 (m, 2H), 1.62(m, 2H), 1.00 (s, 3H), 0.62 (s, 3H).

EXAMPLE 334 6-(1-Hydroxycyclohexyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 629, Structure 105 of Scheme XX, Where R═R¹═R²═R³═R⁴═R⁵═R⁶=H,n=2, Z=Methylene)

This compound was prepared according to General Procedure XIX in Example330 from Compound 308 (Structure 16a of Scheme XX, where R═R¹=H) (1.0 g,3.4 mmol) and cyclohexanone (0.71 mL, 6.8 mmol) to yield 485 mg (46%) ofCompound 629 as a white solid: ¹H NMR (400 MHz, DMSO-d₆) 12.26 (s, 1H),7.88 (s, 1H), 7.75 (dd, J=8.7, 1.5, 1H), 7.38 (d, J=8.6, 1H), 6.96 (s,1H), 4.91 (s, 1H), 1.77-1.62 (mm, 8H), 1.59-1.49 (m, 2H).

EXAMPLE 335 6-Cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound630, Structure 106 of Scheme XX, Where R═R¹═R²═R³═R⁴═R⁵═R⁶=H, n=2,Z=Methylene)

Compound 630 was prepared according to General Procedure XX in Example331 by dehydration of Compound 629 (Structure 105 of Scheme XX, whereR═R¹═R²═R³═R⁴═R⁵═R⁶=H, n=2, Z=methylene) (1.0 g, 3.4 mmol) in 83% yieldas a white solid: ¹H NMR (400 MHz, CDCl₃) 11.07 (bs, 1H), 7.77 (s, 1H),7.65 (dd, J=8.4, 1.5, 1H), 7.29 (d, J=8.6, 1H), 7.07 (s, 1H), 6.17 (bt,1H), 2.43 (m, 2H), 2.25 (m, 2H), 1.81 (m, 2H), 1.68 (m, 2H).

EXAMPLE 336 6-Cyclohexyl-4-trifluoromethyl-2(1H)-thioquinolinone(Compound 631, Structure 108 of Scheme XX, Where R⁴═R⁵=H, n=2,Z=Methylene)

In 10-mL r.b. flask, a solution of Compound 616 (Structure 107 of SchemeXX, where R═R¹⁻⁶=H, n=2, Z=methylene) (39 mg, 0.13 mmol) in toluene (2mL) was treated with Lawsson's reagent (66 mg, 0.16 mmol, 1.2 equiv).The reaction mixture was then stirred at room temperature overnight,diluted with EtOAc (80 mL), washed with sat. NaHCO₃ (15 mL), water (15mL), Brine (15 mL), dried (MgSO₄), filtered and concentrated underreduced pressure to yield crude product. Purification by columnchromatography (15% EtOAc/hexane) afforded 30 mg (73%) of Compound 631as a yellow solid: ¹H NMR (400 MHz, CDCl₃) 11.82 (bs, 1H), 7.71 (s, 1H),7.65 (s, 1H), 7.53 (dd, J=8.6, 1.6, 1H), 7.39 (d, J=8.6, 1H), 2.62 (bs,1H), 1.89-1.76 (mm, 6H), 1.45-1.40 (m, 4H).

EXAMPLE 337 6-Cyclopentenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 632, Structure 106 of Scheme XX, Where R═R¹═R²═R³═R⁴═R⁵═R⁶=H,n=1, Z=Methylene)

This compound was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 308 (Structure 16a of Scheme XX,where R═R¹=H) (50 mg, 0.17 mmol) and cyclopentanone (0.02 mL, 0.26 mmol)to yield 15 mg (31%) of Compound 632 as white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.36 (bs, 1H), 7.88 (dd, J=8.7, 1.4, 1H), 7.55 (s, 1H), 7.41(d, J=8.7, 1H), 6.99 (s, 1H), 6.33 (bm, 1H), 2.68 (m, 2H), 2.51 (m, 2H),1.99 (m, J=6.6, 2H).

EXAMPLE 338 6-Cycloheptenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 633, Structure 106 of Scheme XX, Where R═R¹═R²═R³═R⁴═R⁵═R⁶=H,n=3, Z=Methylene)

Compound 633 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 308 (Structure 16a of Scheme XX,where R═R¹=H) and cycloheptanone as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.31 (s, 1H), 7.63 (d, J=8.7, 1H), 7.51 (s, 1H), 7.39 (d,J=8.6, 1H), 6.98 (s, 1H), 6.11 (t, J=6.7, 1H), 2.57 (m, 2H), 2.29 (m,2H), 1.80 (m, 2H), 1.60 (m, 2H), 1.51 (m, 2H).

EXAMPLE 339 6-Bromo-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone(Compound 634, Structure 16a of Scheme XX, Where R=Fluorine, R¹=H)

In a 100-mL flask a solution of 4-bromoaniline (20 g, 116 mmol) andethyl-4,4,4-trifluoroacetoacetate (25.5 mL, 175 mmol, 1.5 equiv) intoluene (5 mL) is heated to reflux for 5 h, cooled and excess solventremoved to provide N-(4-bromophenyl)-4,4,4-trifluoroacetoacetamide(Structure 15 of Scheme XX). The crude reaction mixture is thendissolved in CH₂Cl₂ (40 mL) and water (10 mL) and then treated withN-fluorobenzenesulfonimide (1.1 equiv) at room temperature overnight.The reaction mixture is then diluted with water (30 mL) and partitioned.The aqueous layer is extracted with CH₂Cl₂ (3×75 mL), the combinedorganic layers are then washed with sat NaHCO₃ (25 mL), saturated NH₄Cl(2×25 mL), water (25 mL), Brine (25 mL), dried (MgSO₄), filtered andconcentrated to affordN-(4-bromophenyl)-2,4,4,4-tetrafluoroacetoacetamide (Structure 15a ofScheme XX). The crude product was then dissolved in concentrated H₂SO₄(10 mL) and heated to 80° C. for 3-4 h, cooled to room temperature, andpoured over NaOH pellets/ice. The cold aqueous solution was thenfiltered, the white precipitate was then redissolved in EtOAc (200 mL),washed with water (2×20 mL), Brine (25 mL), dried (MgSO₄), filtered andconcentrated to yield Compound 634 as a white powder: ¹H NMR (400 MHz,DMSO-d₆) 12.92 (bs, 1H), 7.83 (dd, J=8.0, 1.2, 1H), 7.77 (s, 1H), 7.41(d, J=7.9, 1H).

EXAMPLE 340 6-Cyclohexenyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone(Compound 635, Structure 106 of Scheme XX, Where R=Fluorine,R¹═R²═³═R⁴═R⁵═R⁶=H, n=2, Z=Methylene)

Compound 635 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 634 (Structure 16a of Scheme XX,where R=fluorine, R¹=H) (50 mg, 0.16 mmol) and cyclohexanone (0.030 mL,0.24 mmol) as a white solid in 20% yield: ¹H NMR (400 MHz, DMSO-d₆)12.80 (s, 1H), 7.72 (d, J=8.7, 1H), 7.59 (s, 1H), 7.38 (d, J=8.6, 1H),6.18 (s, 1H), 2.37 (m, 2H), 2.19 (m, 2H), 1.74 (m, 2H), 1.62 (m, 2H).

EXAMPLE 341 6-Cyclohexyl-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 636, Structure 107 of Scheme XX, Where R═R²═R═R⁴═R⁵═R⁶=H,R¹=Methoxy, n=2, Z=Methylene)

6-Bromo-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound 637,Structure 16a of Scheme XX, Where R=H, R¹=Methoxy):

To a 100-mL r.b. flask containing Compound 419 (Structure 29a of SchemeXX) (1.0 g, 4.11 mmol) in DMF (40 mL) was added, in portions, NBS (0.84g, 4.73 mmol, 1.15 equiv). The reaction was allowed to stir overnightand poured into water (25 mL), the resulting precipitate was collectedby vacuum filtration to yield 1.0 g (76%) of Compound 637: ¹H NMR (400MHz, DMSO-d₆) 12.31 (bs, 1H), 7.76 (s, 1H), 7.06 (s, 1H), 6.87 (s, 1H),3.93 (s, 3H).

6-Cyclohexyl-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone (Compound636, Structure 107 of Scheme XX, Where R═R²═R═R⁴═R⁵═R⁶=H, R¹=Methoxy,n=2, Z=Methylene):

This compound is prepared according to General Procedures XIX, XX, andIII in Examples 330, 331 and 1 from Compound 637 (350 mg) andcyclohexanone as a white solid in 38% yield: ¹H NMR (400 MHz, DMSO-d₆)12.17 (bs, 1H), 7.30 (s, 1H), 6.95 (s, 1H), 6.78 (s, 1H), 5.71 (bs, 1H),3.84 (s, 3H), 2.28 (m, 2H), 2.14 (m, 2H), 1.67-1.63 (m, 4H).

EXAMPLE 342 6-Cyclopentyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone(Compound 638, Structure 107 of Scheme XX, Where R=Fluorine,R¹═R²═³═R⁴═R⁵═R⁶=H, n=1, Z=Methylene)

Compound 638 was made according to General Procedures XIX, XX, and IIIin Examples 330, 331 and 1 from Compound 634 (Structure 16a of SchemeXX, where R=fluorine, R¹=H) and cyclopentanone as a white solid: ¹H NMR(400 MHz, DMSO-d₆) 7.53 (m, 2H), 7.38 (d, J=8.4, 1H), 3.07 (quint.,J=8.2, 1H), 2.03 (m, 2H), 1.78 (m, 2H), 1.66 (m, 2H), 1.53 (m, 2H).

EXAMPLE 343(Z)-6-(1-Propyl-1-butenyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound639, Structure 106 of Scheme XX, Where R═R¹═R²═R³═R⁵=H, R⁴=Methyl,R⁶=Ethyl, n=1, Z=Two No-bond Hydrogens) and(E)-6-(1-Propyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound640, Structure 106 of Scheme XX, Where R═R¹═R²═R³═R⁵=H, R⁴=Methyl,R⁶=Ethyl, n=1, Z=Two No-bond Hydrogens)

Compounds 639 and 640 were made according to General ProceduresProcedures XIX and XX in Examples 330 and 331 from Compound 308(Structure 16a of Scheme XX, where R═R¹=H) and 3-hexanone as a 1/2mixture of E/Z isomers, Z-isomer: ¹H NMR (400 MHz, CDCl₃) 11.10 (s, 1H),7.74 (s, 1H), 7.60 (d, J=8.6, 1.5, 1H), 7.40 (d, J=8.6, 1H), 7.06 (s,1H), 5.70 (t, J=7.2, 1H), 2.50 (t, J=7.4, 2H), 2028-2.20 (m, 2H),1.46-1.13 (m, 2H), 1.00 (t, J=7.5, 3H), 0.88 (t, J=7.3, 3H); E-isomer:¹H NMR (400 MHz, CDCl₃) 11.10 (s, 1H), 7.58 (s, 1H), 7.40 (d, J=8.2,1H), 7.32 (d, J=8.2, 1H), 7.06 (s, 1H), 5.53 (t, J=6.9, 1H), 2.33 (t,J=7.5, 2H), 1.96-1.78 (m, 2H), 1.46-1.31 (m, 2H), 0.96 (t, J=7.4, 3H),0.87 (t, J=7.3, 3H).

EXAMPLE 344 6-(1-Propyl)butyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 641, Structure 107 of Scheme XX, Where R═R¹═R²═R³═R⁵=H,R⁴=Methyl, R⁶=Ethyl, n=1, Z=Two No-bond Hydrogens)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compounds 639 and640 (Structure 106 of Scheme XX, where R═R¹═R²═R³═R⁵=H, R⁴=methyl,R⁶=ethyl, n=1, Z=two no-bond hydrogens). Compound 641 was isolated aswhite solid: ¹H NMR (400 MHz, CDCl₃) 11.24 (s, 1H), 7.55 (s, 1H), 7.41(d, J=8.5, 1H), 7.28 (d, J=8.5, 1H), 7.07 (s, 1H), 2.65-2.60 (m, 1H),1.69-1.51 (m, 4H), 1.22-1.10 (m, 4H), 0.85 (t, J=7.3, 6H).

EXAMPLE 345(E)-6-(1-Methyl-1-)butenyl-4-trifluoromethyl-2(1H-quinolinone (Compound642, Structure 106 of Scheme XX, Where R═R¹═R²═R³═R⁴═R⁵=H, R⁶=Ethyl,n=1, Z=Two No-bond Hydrogens) and(Z)-6-(1-Methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound643, Structure 106 of Scheme XX, Where R═R¹═R²═R³═R⁴═R⁵=H, R⁶=Ethyl,n=1, Z=Two No-bond Hydrogens)

Compounds 642 and 643 were made according to General Procedures XIX andXX in Examples 330 and 331 from Compound 308 (Structure 16a of SchemeXX, where R═R¹=H) and 2-pentanone as a 5/2 mixture of E/Z isomers:E-isomer: ¹H NMR (400 MHz, CDCl₃) 10.97 (s, 1H), 7.78 (s, 1H), 7.67 (d,J=8.5, 1H), 7.28 (d, J=8.5, 1H), 7.07 (s, 1H), 5.81 (t, J=7.2, 1H), 2.25(m, 2H), 2.10 (s, 3H), 1.09 (t, J=7.6, 3H); Z-isomer: ¹H NMR (400 MHz,CDCl₃) 11.43 (s, 1H), 7.64 (d, J=1.3, 1H), 7.46 (dd, J=8.6, 1.3, 1H),7.33 (d, J=8.6, 1H), 7.08 (s, 1H), 5.56 (t, J=7.4, 1H), 2.06 (s, 3H),2.01-1.94 (m, 2H), 0.96 (t, J=7.4, 3H).

EXAMPLE 346 (±)-6-(1-Methyl)butyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 644, Structure 107 of Scheme XX, Where R═R¹═R²═R³═R⁴═R⁵=H,R⁶=Ethyl, n=1, Z=Two No-bond Hydrogens)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compounds 642 and643 (Structure 106 of Scheme XX, where R═R¹═R²═R³═R⁴═R⁵=H, R⁶=ethyl,n=1, Z=two no-bond hydrogens). Compound 644 was isolated as a whitesolid: ¹H NMR (400 MHz, CDCl₃) 11.40 (s, 1H), 7.26 (s, 1H), 7.45 (d,J=8.5, 1H), 7.33 (d, J=8.5, 1H), 7.07 (s, 1H), 2.82-2.78 (m, 1H), 1.58(q, J=7.7, 2H), 1.25 (d, J=4.1, 3H), 1.20-1.10 (m, 2H), 0.88 (t, J=7.2,3H).

EXAMPLE 347(E)-6-(1-Ethyl-1-)propenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound645, Structure 106 of Scheme XX, Where R═R¹═R²═R³═R⁴═R⁵=H, R⁶=Methyl,n=1, Z=Two No-bond Hydrogens) and(Z)-6-(1-Ethyl-1-)propenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound646, Structure 106 of Scheme XX, Where R═R¹═R²═R³═R⁴═R⁵=H, R⁶=Methyl,n=1, Z=Two No-bond Hydrogens)

Compounds 645 and 646 were made according to General Procedures XIX andXX in Examples 330 and 331 from Compound 308 (Structure 16a of SchemeXX, where R═R¹=H) and 3-pentanone as a 2/3 mixture of E/Z isomers:E-isomer: ¹H NMR (400 MHz, CDCl₃) 11.10 (s, 1H), 7.62-7.59 (m, 1H), 7.42(d, J=8.8, 1H), 7.33 (d, J=8.8, 1H), 7.08 (s, 1H), 5.77 (q, J=7.1, 1H),2.55 (q, J=7.8, 2H), 1.83 (d, J=7.1, 3H), 1.02 (m, 3H); Z-isomer: ¹H NMR(400 MHz, CDCl₃) 11.10 (s, 1H), 7.75 (s, 1H), 7.42 (d, J=8.8, 1H), 7.33(d, J=8.8, 1H), 7.07 (s, 1H), 5.63 (q, J=6.9, 1H), 2.38 (q, J=7.8, 2H),1.52 (d, J=7.1, 3H), 1.02 (m, 3H).

EXAMPLE 348 6-(1-Ethylpropyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 647, Structure 107 of Scheme XX, Where R═R¹═R²═R³═R⁴═R⁵=H,R⁶=Methyl, n=1, Z=Two No-bond Hydrogens)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compounds 645 and646 (Structure 106 of Scheme XX, where R═R¹═R²═R³═R⁴═R⁵=H, R⁶=methyl,n=1, Z=two no-bond hydrogens). Compound 476 was isolated as white solid:¹H NMR (400 MHz, CDCl₃) 12.01 (s, 1H), 7.56 (s, 1H), 7.41 (dd, J=8.3,1.5, 1H), 7.39 (d, J=8.3, 1H), 7.08 (s, 1H), 2.87-2.68 (m, 1H),1.52-1.25 (m, 4H), 0.78 (t, J=7.3, 6H).

EXAMPLE 3496-(1-Isopropyl-2-methyl-1-)propenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 648, Structure 106 of Scheme XX, Where R═R¹═R³═R⁴=H,R²═R⁵═R⁶=Methyl, n=1, Z=Two No-bond Hydrogens)

Compound 648 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 308 (Structure 16a of Scheme XX,where R═R¹=H) and 2,4-dimethyl-3-pentanone as a white solid: ¹H NMR (400MHz, CDCl₃) 11.10 (s, 1H), 7.47 (d, J=8.4, 1H), 7.45 (s, 1H), 7.27 (d,J=8.4, 1H), 7.11 (s, 1H), 3.12-3.07 (m, 1H), 1.85 (s, 3H), 1.38 (s, 3H),0.88 (d, J=6.8, 6H).

EXAMPLE 3506-(1-Isopropyl-2-methyl)propyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 649, Structure 107 of Scheme XX, Where R═R¹═R³═R⁴=H,R²═R⁵═R⁶=Methyl, n=1, Z=Two No-bond Hydrogens)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compound 648(Structure 106 of Scheme XX, where R═R¹═R³═R⁴=H, R²═R⁵═R⁶=methyl, n=1,Z=two no-bond hydrogens). Compound 649 was isolated as white solid: ¹HNMR (400 MHz, CDCl₃) 11.10 (s, 1H), 7.52 (s, 1H), 7.36 (d, J=8.5, 1H),7.31 (d, J=8.5, 1H), 7.07 (s, 1H), 2.21-2.15 (m, 3H), 0.87 (d, J=6.5,6H), 0.74 (d, J=6.5, 6H).

EXAMPLE 351(Z)-6-(1-Isobutyl-3-methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 650, Structure 106 of Scheme XX, Where R═R¹═R²═R⁵=H,R³═R⁴=Methyl, R⁶=Isopropyl, n=1, Z=Two No-bond Hydrogens) and(E)-6-(1-Isobutyl-3-methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 651, Structure 106 of Scheme XX, Where R═R¹═R²═R⁵=H,R³═R⁴=Methyl, R⁶=Isopropyl, n=1, Z=Two No-bond Hydrogens)

Compound 650 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 308 (Structure 16a of Scheme XX,where R═R¹=H) and 2,6-dimethyl-4-heptanone as a white solid: ¹H NMR (400MHz, CDCl₃) 11.10 (s, 1H), 7.58 (s, 1H), 7.40 (s, 2H), 7.09 (s, 1H),5.31 (d, J=10.1, 1H), 2.32-2.24 (m, 1H), 2.24 (d, J=7.2, 2-H), 1.49-1.44(m, 1H), 0.94 (d, J=6.6, 6H), 0.84 (d, J=6.6, 6H).

Compound 651 was also isolated as a white solid: ¹H NMR (400 MHz, CDCl₃)11.10 (s, 2H), 7.73 (s, 1H), 7.62 (s, 1H), 7.11 (s, 1H), 5.53 (d, J=9.6,1H), 2.78-2.69 (m, 1H), 2.44 (d, J=7.2, 2H), 1.60-1.51 (m, 1H), 1.06 (d,J=6.6, 6H), 0.84 (d, J=6.6, 6H).

EXAMPLE 3526-Isobutyl-3-methyl)butyl-4-trifluoromethyl-2(1H)-quinolinone (Compound652, Structure 107 of Scheme XX, Where R═R¹═R²═R⁵ 32 H, R³═R⁴=Methyl,R⁶=Isopropyl, n=1, Z=Two No-bond Hydrogens)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compound 650(Structure 106 of Scheme XX, where R═R¹═R²═R⁵=H, R³═R⁴=methyl,R⁶=isopropyl, n=1, Z=two no-bond hydrogens). Compound 652 was isolatedas a white solid: ¹H NMR (400 MHz, CDCl₃) 11.31 (s, 1H), 7.56 (s, 1H),7.41 (d, J=8.2, 1H), 7.35 (d, J=8.2, 1H), 7.04 (s, 1H), 2.82-2.78 (m,1H), 1.55-1.38 (m, 4H), 1.32-1.25 (m, 2H), 0.86 (d, J=6.4, 6H), 0.81 (d,J=6.4, 6H).

EXAMPLE 353 6-(1-Propyl)butyl-4-trifluoromethyl-2(1H)-thioquinolinone(Compound 653, Structure 108 of Scheme XX, Where R⁴═R⁵=Methyl, n=1,Z=Two No-bond Hydrogens)

This compound was prepared in a similar method as that described inExample 95, General Procedure XI but using Compound 641 (Structure 107of Scheme XX, where R═R¹═R²═R³═R⁵=H, R⁴=methyl, R⁶=ethyl, n=1, Z=twono-bond protons) in place of Compound 209. Compound 653 was isolated asa yellow solid: ¹H NMR (400 MHz, CDCl₃) 11.91 (s, 1H), 7.76 (s, 1H),7.69 (s, 1H), 7.48 (d, J=8.5, 1H), 7.41 (d, J=8.5, 1H), 2.69-2.63 (m,1H), 1.73-1.51 (m, 4H), 1.21-1.04 (m, 4H), 0.82 (t, J=7.2, 6H).

EXAMPLE 3546-(3-Oxo-1-)Cyclopentenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound654, Structure 109 of Scheme XXI, Where R=H, R¹=Trifluoromethyl, n=0)

Compound 654 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 308 (Structure 16b of Scheme XXI,where R=H) and 3-ethoxy-2-cyclopentenone as a white solid: ¹H NMR (400MHz, CDCl₃) 11.06 (s, 1H), 8.07 (s, 1H), 7.91 (d, J=8.6, 1H), 7.46 (d,J=8.8, 1H), 7.14 (s, 1H), 6.64 (s, 1H), 3.18-3.10 (m, 2H), 2.70-2.53 (m,2H).

EXAMPLE 355 6-(3-oxo-1-)Cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 655, Structure 109 of Scheme XXI, Where R=H,R¹=Trifluoromethyl, n=1)

Compound 655 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 308 (Structure 16b of Scheme XXI,where R=H) and 3-ethoxy-2-cyclohexenone as a white solid: ¹H NMR (400MHz, CDCl₃) 11.06 (s, 1H), 7.97 (s, 1H), 7.79 (d, J=8.7, 1H), 7.47 (d,J=8.7, 1H), 7.13 (s, 1H), 6.47 (s, 1H), 2.85-2.81 (m, 2H), 2.54-2.51 (m,2H), 2.27-2.21 (m, 2H), 2.27-2.21 (m, 2H).

EXAMPLE 3566-(3-oxo-1-)Cyclopentenyl-3-methyl-4-difluoromethyl-2(1H)-quinolinone(Compound 656, Structure 109 of Scheme XXI, Where R=Methyl,R¹=Difluoromethyl, n=0)

To a suspension of Compound 308 (Structure 16b of Scheme XXI, where R=H)(250 mg, 0.90 mmol) in THF (4 mL) at −40° C., MeLi 1.4 M in ether (1.5equiv) was added followed by n-BuLi 1.6 M in hexane (1.1 equiv). Asolution of 3-ethoxy-2-cyclopentenone (1.1 equiv) in 1-5 THF (3 mL) wasslowly added to this thick suspension via canula. The mixture wasallowed to worm up slowly to room temperature and was allowed to stirover night. The reaction was quenched by HCl 10% until PH˜1 then theorganic layer was taken into EtOAC (3×20 mL), washed with brine (20 mL),and dried over Na₂SO₄. The solvent was removed under reduced pressureand the residue was crystallized out from EtOAc/EtOH. The resulting cakewas further purified by HPLC reverse phase (MeOH/H₂O/Et₃N:60/40/0.5) togive Compound 656 as a white solid: ¹H NMR (400 MHz, DMSO-d₆) 11.20 (s,1H), 8.24 (d, J=1.6, 1H), 7.99 (dd, J=1.6, 8.6, 1H), 7.67 (t, J=5.1,1H), 7.43 (d, J=8.6, 1H), 6.71 (d, J=1.3, 1H), 3.06-3.01 (m, 2H),2.48-2.43 (m, 2H), 2.29 (s, 3H).

EXAMPLE 3576-(3-Oxo-1-)Cyclohexenyl-3-methyl-4-difluoromethyl-2(1H)-quinolinone(Compound 657, Structure 109 of Scheme XXI, Where R=Methyl,R¹=Difluoromethyl, n=1)

This compound was prepared in a similar fashion as that described inExample 356 but using 3-ethoxy-2-cyclohexenone in place of3-ethoxy-2-cyclopentenone. Compound 657 was isolated as a white solid:¹H NMR (400 MHz, CDCl₃) 10.15 (s, 1H), 8.24 (s, 1H), 7.70 (d, J=9.1,1H), 7.27 (d, J=9.1, 1H), 7.17 (t, J=5.9, 1H), 6.48 (s, 1H), 2.85-2.78(m, 2H), 2.55-2.49 (m, 2H), 2.42 (s, 3H), 2.24-2.18 (m, 2H).

EXAMPLE 358(±)-6-(3-Hydroxy-1-)cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 658, Structure 110 of Scheme XXI, Where R=H,R¹=Trifluoromethyl, n=1)

This compound was prepared by the following General Procedure XXI(Reduction of ketone):

To a solution of a ketone in dry THF (0.1-0.5 M) at ˜78° C. was added a2 equiv of 1.5 M DIBAL/toluene solution. After 30 min., the reactionmixture was quenched with saturated NH₄Cl and extracted with EtOAc. Theorganic layer was washed with H₂O (3×) and brine (3×), dried (Na₂SO₄)and concentrated in vacuo. Purification by flash chromatography affordedthe alcohol as a white solid in good yield.

Compound 658 was isolated as a white solid: ¹H NMR (400 MHz, DMSO-d₆)11.20 (s, 1H), 7.77 (dd, J=8.8, 1.4, 1H), 7.62 (d, J=1.4, 1H), 7.41 (d,J=8.8, 1H), 6.99 (s, 1H), 6.10 (s, 1H), 4.82 (d, J=5.5, 2H), 2.37-2.27(m, 2H), 1.90-1.87 (m, 2H), 1.71-1.65 (m, 1H), 1.53-1.44 (m, 1H).

EXAMPLE 3596-(1-Hydroxy-1,1-diphenyl)methyl-4-trifluoromethyl-2(1H-quinolinone(Compound 659, Structure 111 of Scheme XXII)

Compound 659 was made according to General Procedures XIX in Examples330 from Compound 308 (Structure 16 of Scheme XXII) and benzophenone asa white solid: ¹H NMR (400 MHz, CDCl₃) 10.89 (s, 1H), 7.78 (d, J=1.8,1H), 7.61 (dd, J=8.5, 1.8, 1H), 7.42 (d, J=8.5, 1H), 7.37-7.28 (m, 10H),7.04 (s, 1H), 3.02 (s, 1H).

EXAMPLE 360 6-Diphenylmethyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 660, Structure 112 of Scheme XXII)

To a solution of Compound 659 (Structure 111 of Scheme XXII) indichloroethane was added an excess of TFA followed by an excess oftriethylsilane. This mixture was allowed to stir over night at roomtemperature. Quenched by water the organic layer was taken into EtOAcwashed with brine, dried over Na₂SO₄. The solvent was removed underreduced pressure. The resulting residue was purified by flash columnchromatography to yield Compound 660 as a white solid: ¹H NMR (400 MHz,CDCl₃) 1.10 (s, 1H), 7.55 (s, 1H), 7.41 (d, J=8.5, 1H), 7.35-7.24 (m,10H), 7.33 (d, J=7.1, 4H), 7.04 (s, 1H), 5.63 (s, 1H).

EXAMPLE 3616-(3-Hydroxy-3-methyl-1-)butynyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 661, Structure 113 of Scheme XXII)

To a solution of Compound 308 (Structure 16 of Scheme XXII) (26 mg,0.090 mmol), triphenylphosphine (152 mg, 0.06 mmol), CuI (4.2 mg, 0.02mmol), 2-methyl-2-butynol (8.5 mg, 0.10 mmol) in triethylamine (1 mL)was added PdCl₂ (0.2 mg, 0.001 mmol) and the reaction mixture was heatedat reflux for 20 min. Pyridine (0.3 mL) was added and the reaction washeated for additional hour. The reaction was quenched with 2 N HCl (20mL), extracted with EtOAc (20 mL), and concentrated. Removal of solventand chromatography of the crude residue afforded Compound 661 in 60%yield as a white solid: ¹H NMR (500 MHz, DMSO-d₆) 12.5 (bs, 1H), 7.62(d, J=8.8, 1H), 7.59 (s, 1H), 7.41 (d, J=8.8, 1H), 7.04 (s, 1H), 5.49(s, 1H), 1.46 (s, 6H).

EXAMPLE 3626-(1-Hydroxy)cyclopentyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 662 Structure 115 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H,n=1, Z=Methylene)

6-Bromo-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound 663,Structure 114 of Scheme XXIII):

To a solution of Compound 486 (Structure 49a of Scheme XXIII) (0.46 g,2.6 mmol) and CCl₄ (20 mL) was added bromine (0.13 mL). Stirred at roomtemperature for 1.5 hrs. The reaction mixture was concentrated in vacuoto afford an orange solid. Washed solid with hot hexane and filtered toafford 0.61 g of Compound 663 in 91% yield as a light orange solid: ¹HNMR (400 MHz, CDCl₃) 8.03 (br s, 1H), 7.37 (dd, J=1.9, 8.3, 1H), 7.26 (dunder solvent peak, 1H), 6.69 (d, J=8.3, 1H), 1.71 (s, 6H).

6-(1-Hydroxy)cyclopentyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 662, Structure 115 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H,n=1, Z=Methylene):

Compound 662 was prepared according to General Procedure XIX in Example330 from Compound 663 (50 mg, 0.20 mmol) and cyclopentanone (0.02 mL,0.24 mmol) in 44% yield (23 mg) as a white solid: ¹H NMR (400 MHz,CD₃OD) 7.36 (d under dd, 2H), 6.83 (d, J=8.0, 1H), 5.48 (s, 1H), 1.95(m, 6H), 1.83 (m, 2H), 1.67 (s, 6H).

EXAMPLE 3636-(1-Cyclopentenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 664, Structure 116 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H,n=1, Z=Methylene)

This compound was prepared in a similar fashion as that described inExample 331, General Procedure XX from Compound 662 (Structure 115 ofScheme XXIII, where R⁴═R⁵═R⁶═R⁷═R⁸=H, n=1, Z=methylene). Compound 664was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.14 (br s, 1H),7.30 (dd, J=1.4, 8.3, 1H), 7.18 (d, J=1.4, 1H), 6.75 (d, J=8.3, 1H),6.12 (m, 1H), 2.67 (m, 2H), 2.53 (m, 2H), 2.02 (quintet, J=7.3, 2H),1.73 (s, 6H).

EXAMPLE 3646-Cyclopentyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 665, Structure 118 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H,n=1, Z=Methylene)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compound 664(Structure 116 of Scheme XXIII, where R⁴═R⁵═R⁶═R⁷═R⁸=H, n=1,Z=methylene). Compound 665 was isolated as a white solid: ¹H NMR (400MHz, CDCl₃) 8.79 (br s, 1H), 7.09 (d, J=8.1, 1H), 6.97 (s, 1H), 6.77 (d,J=8.1, 1H), 2.95 (m, 1H), 2.05 (m, 2H), 1.80 (m, 2H), 1.69 to 1.62 (m,10H).

EXAMPLE 3656-(1-Hydroxy)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 666, Structure 115 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H,n=2, Z=Methylene)

This compound was prepared according to General Procedure XIX in Example330 from Compound 663 (Structure 114 of Scheme XXIII) and cyclohexanoneas a white solid; ¹H NMR (400 MHz, CDCl₃) 7.33 (m, 2H), 6.72 (d, J=8.6,1H), 1.76 to 1.60 (m, 1.6H).

EXAMPLE 3666-(1-Cyclohexenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 667, Structure 116 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H,n=2, Z=Methylene)

This compound was prepared in a similar fashion as that described inExample 331, General Procedure XX by dehydration of Compound 666(Structure 115 of Scheme XXIII, where R⁴═R⁵═R⁶═R⁷═R⁸=H, n=2,Z=methylene). Compound 667 was isolated as a white solid: ¹H NMR (400MHz, CDCl₃) 7.49 (br s, 1H), 7.24 (dd, J=1.4, 8.2, 1H), 7.14 (d, J=1.4,1H), 6.70 (d, J=8.2, 1H), 6.05 (m, 1H), 2.36 (m, 2H), 2.20 (m,. 2H),1.79 to 1.76 (m, 2H), 1.72 (s, 6H), 1.67 to 1.60 (m, 2H).

EXAMPLE 3676-Cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one (Compound668, Structure 118 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H, n=2,Z=Methylene)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compound 667(Structure 116 of Scheme XXIII, where R⁴═R⁵═R⁶═R⁷═R⁸=H, n=2,Z=methylene). Compound 668 was isolated as a white solid: ¹H NMR (400MHz, CDCl₃) 8.61 (br s, 1H), 7.10 (dd, J=1.4, 8.2, 1H), 6.93 (d, J=1.4,1H), 6.78 (d, J=8.2, 1H), 2.45 (m, 1H), 1.98 (m, 5H), 1.71 (s, 6H), 1.38to 1.20 (m, 5H).

EXAMPLE 3686-(1-Hydroxycycloheptyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 669, Structure 115 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H,n=3, Z=Methylene)

This compound was prepared according to General Procedure XIX in Example330 from Compound 663 (Structure 114 of Scheme XXIII) and cycloheptanoneas a white solid: ¹H NMR (400 MHz, CDCl₃) 8.90 (br s, 1H), 7.31 (d underdd, 2H), 6.80 (d, J=8.7, 1H), 2.04 (m, 2H), 1.80 (m, 2H), 1.78 to 1.56(m, 14H).

EXAMPLE 3696-(1-Cycloheptenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 670, Structure 116 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H,n=3, Z=Methylene)

This compound was prepared in a similar fashion as that described inExample 331, General Procedure XX by dehydration of Compound 669(Structure 115 of Scheme XXIII, where R⁴═R⁵═R⁶═R⁷═R⁸=H, n=3,Z=methylene). Compound 670 was isolated as a white solid: ¹H NMR (400MHz, CDCl₃) 8.86 (br s, 1H), 7.17 (dd, J=1.7, 8.2, 1H), 7.05 (d, J=1.7,1H), 6.77 (d, J=8.2, 1H), 6.03 (t, J=6.7, 1H), 2.56 (m, 2H), 2.28 (m,2H), 1.85 (m, 2H), 1.73 (s, 6H), 1.65 (m, 4H).

EXAMPLE 3706-(1-Cycloheptyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 671, Structure 118 of Scheme XXIII, Where R⁴═R⁵═R⁶═R═R⁸=H,n=3, Z=Methylene)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compound 670(Structure 116 of Scheme XXIII, where R⁴═R⁵═R⁶═⁷=H, n=3, Z=methylene).Compound 671 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.34(br s, 1H), 7.05 (d, J=8.1, 1H), 6.92 (s, 1H), 6.73 (d, J=8.1, 1H), 2.62(m, 1H), 1.85 to 1.51 (m, 24H).

EXAMPLE 3716-(2,6,6-Trimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 672. Structure 116 of Scheme XXIII, Where R⁴═R⁷R⁸=Methyl,R⁵═R⁶=H, n=2, Z=Methylene)

This compound was prepared in a similar fashion as that described inExamples 330 and 331, General Procedures XIX and XX by using Compound663 (Structure 114 of Scheme XXIII) and 2,2,6-trimethylcyclohexanone.Compound 672 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 9.85(br s, 1H), 8.21 (d, J=8.4, 1H), 7.30 (d under dd, 2H), 5.92 (s, 1H),2.38 (m, 2H), 2.18 (s, 3H), 1.85 (m, 2H), 1.75 (m, 8H), 1.33 (s, 3H).

EXAMPLE 372(±)-6-(3,3,5-Trimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 673, Structure 116 of Scheme XXIII, Where R⁴═R⁷═R⁸=H,R⁵═R⁶=Methyl, n=1, Z=2-Methylethylene) and(±)-6-(3,5,5-Trimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 674, Structure 116 of Scheme XXIII, Where R⁴═R⁵═R⁷═R⁸=H,R⁶=Methyl, n=1, Z=2,2-Dimethylethylene)

These compounds were prepared in a similar fashion as that described inExamples 330 and 331, General Procedures XIX and XX by using Compound663 (Structure 114 of Scheme XXIII) and 3,3,5-trimethylcyclohexanone.Compounds 673 and 674 were isolated as a 1/1 mixture as a white solid:¹H NMR (400 MHz, CDCl₃) 8.60 (br s, 2H), 7.24 (dd, J=2.0, 8.1, 2H), 7.13(d, J=2.0, 2H), 6.78 (d, J=8.1, 2H), 5.85 (s, 1H), 5.74 (s, 1H), 2.35(m, 2H), 2.20 (m, 2H), 2.04 (m, 2H), 1.92 (m, 2H), 1.74 (s, 6H), 1.73(s, 6H), 1.51 (m, 4H), 1.08 (m, 18H).

EXAMPLE 373(±)-6-(5-Methyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 675, Structure 116 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H,n=2, Z=Methylmethine) and(±)-6-(3-Methyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 676, Structure 116 of Scheme XXIII, Where R⁴═R⁶═R⁷═R⁸=H,R⁵=Methyl, n=1, Z=Ethylene)

These compounds were prepared in a similar fashion as that described inExamples 330 and 331, General Procedures XIX and XX by using Compound663 (Structure 114 of Scheme XXIII) and ³-methylcyclohexanone. Compounds675 and 676 were isolated as a 2/1 mixture as a white solid: ¹H NMR (400MHz, CDCl₃) 8.62 (br s, 2H), 7.25 (dd, J=2.0, 8.2, 2H), 7.14 (d, J=2.0,2H), 6.77 (d, J=8.2, 2H), 6.04 (s, 1H), 5.89 (s, 1H), 2.43 to 2.25 (m,13H), 1.73 (s, 6H), 1.72 (s, 6H), 1.07 (m, 6H).

EXAMPLE 374(±)-6-(2,6-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 677, Structure 116 of Scheme XXIII, Where R⁴═R⁸=Methyl,R⁵═R⁶═R⁷=H, n=2, Z=Methylene)

This compound was prepared in a similar fashion as that described inExamples 330 and 331, General Procedures XIX and XX by using Compound663 (Structure 114 of Scheme XXIII) and 2,6-dimethylcyclohexanone.Compound 677 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.86(br s, 1H), 6.94 (dd, J=1.6, 8.0, 1H), 6.85 (d, J=1.6, 1H), 6.73 (d,J=8.0, 1H), 2.42 (br m, 1H), 2.05 (m, 2H), 1.81 (m, 1H), 1.71 (s, 3H),1.70 (s, 3H), 1.65 (m, 2H), 1.47 (s, 3H), 0.79 (d, J=6.9, 3H).

EXAMPLE 375(±)-6-(2-Bicyclo[2.2.1]heptenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 678, Structure 116 of Scheme XXIII, Where R⁵R⁸=BridgedEthylene, R⁴═R⁵═R⁸=H, n=1, Z=Methylene)

This compound was prepared in a similar fashion as that described inExamples 330 and 3-331, General Procedures XIX and XX by using Compound663 (Structure 114 of Scheme XXIII) and 2-norbornanone. Compound 678 wasisolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 8;44 (br s, 1H), 7.28(d, J=8.3, 1H), 7.16 (s, 1H), 6.77 (d, J=8.3, 1H), 6.22 (d, J=3.0, 1H),3.27 (s, 1H), 3.00 (s, 1H), 1.83 (m, 2H), 1.77 (s, 3H), 1.76 (s, 3H),1.52 (m, 1H), 1.25 (m, 1H), 1.10 (m, 2H).

EXAMPLE 376(±)-6-(4,5-trans-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 679, Structure 116 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H,n=1, Z=1,2-trans-Dimethylethylene) and(±)-6-(3,4-trans-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 680, Structure 116 of Scheme XXII, Where R⁴═R⁶═R⁷═R⁸=H,R⁵=Methyl, n=1, Z=2-Methylethylene)

These compounds were prepared in a similar fashion as that described inExamples 330 and 331, General Procedures XIX and XX by using Compound663 (Structure 114 of Scheme XXIII) and trans-3,4-dimethylcyclohexanone.Compounds 679 and 680 were isolated as a 2/1 mixture as a white solid:¹H NMR (400 MHz, CDCl₃) 8.68 (br s, 2H), 7.25 (dd, J=1.8, 8.4, 2H), 7.14(d, J=1.8, 2H), 6.78 (d, J=8.4, 2H), 6.00 (brt, 1H), 5.83 (s, 1H), 2.35to 2.25 (m, 4H), 2.05 (m, 4H), 1.85 (m, 4H), 1.73 (s, 6H), 1.72 (s, 6H),1.26 (m, 2H), 1.03 (m, 12H).

EXAMPLE 3776-(6,6-Dimethyl-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 681, Structure 116 of Scheme XXIII, Where R⁷═R⁸=Methyl,R⁴═R¹═R=H, n=2, Z=Methylene)

This compound was prepared in a similar fashion as that described inExamples 330 and 331, General Procedures XIX and XX by using Compound663 (Structure 114 of Scheme XXIII) and 2,2-dimethylcyclohexanone.Compound 681 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.53(br s, 1H), 6.99 (dd, J=1.7, 8.0, 1H), 6.88 (d, J=1.7, 1H), 6.73 (d,J=8.0, 1H), 5.42 (t, J=3.7, 1H), 2.11 (m, 2H), 1.71 (m, 8H), 0.99 (s,6H).

EXAMPLE 3786-(5,5-Dimethyl-1-)cyclopentenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 682, Structure 116 of Scheme XXIII, Where R⁷═R⁸=Methyl,R⁴═R⁵═R⁶=H, n=1, Z=Methylene)

This compound was prepared in a similar fashion as that described inExamples 330 and 331, General Procedures XIX and XX by using Compound663 (Structure 114 of Scheme XXIII) and 2,2-dimethylcyclopentanone.Compound 511 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.02(br s, 1H), 7.19 (dd, J=1.8, 8.1, 1H), 7.09 (d, J=1.8, 1H), 6.73 (d,J=8.1, 1H), 5.70 (t, J=2.4, 1H), 2.36 (td, J=2.5, 7.1, 1H), 1.86 (t,J=7.1, 1H), 1.72 (s, 6H), 1.18 (s, 6H).

EXAMPLE 379(±)-6-(3,3,5-cis-Trimethyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 683, Structure 118 of Scheme XXIII, Where R⁴═R⁷═R⁸=H,R⁵═R⁶=Methyl, n=1, Z=2-Methylethylene) and(±)-6-(3,3,5-trans-Trimethyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 684, Structure 118 of Scheme XXIII, Where R⁴═R⁷═R⁸=H,R⁵═R⁶=Methyl, n=1, Z=2-Methylethylene)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compounds 673/674(Structure 116 of Scheme XXIII, where R⁴═R⁷═R⁸=H, R⁵═R⁶=methyl, n=1,Z=2-methylethylene). Compounds 683 and 684 were isolated as a 2/1mixture as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.39 (br s, 2H), 7.15(dd, J=1.7, 8.2, 1H), 7.07 (dd, J=1.7, 8.2, 1H), 6.97 (d, J=1.7, 1H),6.92 (d, J=1.7, 1H), 6.75 (d, J=8.2, 2H), 2.90 (m, 1H), 2.70 (m, 1H),2.05 (m, 1H), 1.72 (s, 12H).

EXAMPLE 380(±)-6-(3-cis-Methyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 685, Structure 118 of Scheme XXIII, Where R⁴═R⁶═R⁷═R⁸=H,R⁵=Methyl, n=1, Z=2-Ethylene) and(±)-6-(3-trans-Methyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 686, Structure 118 of Scheme XXIII, Where R⁴═R⁶═R⁷═R⁸=H,R⁵=Methyl, n=1, Z=Ethylene)

These compounds were prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of compounds 675/676(Structure 116 of Scheme XXIII, where R⁴═R⁶═R⁷═R¹=H, R⁵=methyl, n=1,Z=ethylene). Compounds 685 and 686 were isolated as a 2/1 mixture as awhite solid: (major isomer) ¹H NMR (400 MHz, CDCl₃) 7.86 (bs, 1H), 7.08(dd, J=8.4, 2.1, 1H), 6.95 (d, J=2.1, 1H), 6.75 (d, J=8.4, 1H), 2.59 (m,1H), 2.05 (m, 1H), 1.88-1.28 (m, 8H), 1.72 (s, 6H), 0.94 (d, J=7.5, 3H);(minor isomer) ¹H NMR (400 MHz, CDCl₃) 7.86 (bs, 1H), 7.10 (dd, J=8.4,2.1, 1H), 6.97 (d, J=2.1, 1H), 6.75 (d, J=8.4, 1H), 2.79 (m, 1H), 2.05(m, 1H), 1.88-1.28 (m, 8H), 1.72 (s, 6H), 1.08 (d, J=7.5, 3H).

EXAMPLE 381(±)-6-(2,6-cis,cis-Dimethyl)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 687, Structure 118 of Scheme XXIII, Where R⁵═R⁶═R⁷=H,R⁴═R⁸=Methyl, n=1, Z=Ethylene)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compound 677(Structure 116 of Scheme XXIII, where R⁴═R⁸=methyl, R⁵═R⁶═R⁷=H, n=2,Z=methylene). Compound 687 was isolated as a white solid: ¹H NMR (400MHz, CDCl₃) 7.36 (br s, 1H), 7.17 (d, J=8.2, 1H), 7.02 (s, 1H), 6.65 (d,J=8.2, 1H), 2.74 (m, 1H), 1.86 (m, 2H), 1.71 (s, 6H), 1.50to 1.40 (m,4H), 0.63 (d, J=7.1, 6H).

EXAMPLE 382(E)-6-(1,4-Dimethyl-1-)pentenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 688, Structure 116 of Scheme XXIII, Where R⁴=Methyl,R⁶=Isopropyl, R⁵═R⁷═R⁸=H, n=1, Z=Two No-bond Hydrogens)

This compound was prepared in a similar fashion as that described inExamples 330 and 331, General Procedures XIX and XX by using Compound663 (Structure 114 of Scheme XXIII) and 5-methyl-2-hexanone. Compound688 was isolated as a colorless oil: ¹H NMR (400 MHz, CDCl₃) 8.92 (br s,1H), 7.23 (dd, J=1.7, 8.0, 1H), 7.11 (d, J=1.7, 1H), 6.79 (d, J=8.0,1H), 5.73 (t, J=8.0, 1H), 2.07 (t, J=8.0, 2H), 1.94 (s, 3H), 1.71-1.73(m, 3H), 1.72 (s, 6H), 0.96 (s, 3H), 0.94 (s, 3H).

EXAMPLE 3836-(1-Cyclohexenyl)-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione(Compound 689, Structure 117 of Scheme XXIII, Where R⁴═R⁵═R⁶═R⁷═R⁸=H,n=2, Z=Methylene)

This compound was prepared in a similar method as that described inExample 95, General Procedure XI by treatment of Compound 667 (Structure116 of Scheme XXIII, where R⁴═R⁵═R⁶═R⁷═R⁸=H, n=2, Z=methylene) withLawesson's reagent. Compound 689 was isolated as a white solid: ¹H NMR(400 MHz, CDCl₃) 9.60 (br s, 1H), 7.29 (dd, J=1.8, 8.2, 1H), 7.13 (d,J=1.8, 1H), 6.81 (d, J=8.2, 1H), 6.08 (t, J=4.0, 1H), 2.35 (m, 2H), 2.20(m, 2H), 1.80 to 1.76 (m, 8H), 1.68 to 1.60 (m, 2H).

EXAMPLE 3846-(3-Oxo-1-)Cyclopentenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 690, Structure 119 of Scheme XXIV, Where Y=O, n=0)

Compound 690 was made according to Examples 330 and 331, GeneralProcedures XIX and XX by using Compound 663 (Structure 114 of SchemeXXIV) and 3-ethoxy-2-cyclopenten-1-one as a white solid: ¹H NMR (400MHz, CDCl₃) 8.53 (br s, 1H), 7.56 (dd, J=1.8, 8.3, 1H), 7.42 (d, J=1.8,1H), 6.91 (d, J=8.3, 1H), 6.52 (s, 1H), 3.02 (m, 2H), 2.60 (m, 2H), 1.75(s, 6H).

EXAMPLE 3856-(3-Oxo-1-)Cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 691, Structure 119 of Scheme XXIV, Where Y=O, n=1)

Compound 691 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 663 (Structure 114 of Scheme XXIV)and 3-ethoxy-2-cyclohexen-1-one as a white solid: ¹H NMR (400 MHz,CDCl₃) 8.05 (br s, 1H), 7.44 (dd, J=1.9, 8.3, 1H), 7.34 (d, J=1.9, 1H),6.85 (d, J=8.3, 1H), 6.34 (s, 1H), 2.75 (t, J=5.4, 2H), 2.49 (t, J=5.4,2H), 2.16 (quintet, J=5.4, 2H), 1.75 (s, 6H).

EXAMPLE 386(±)-6-(3-Hydroxy-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 692, Structure 120 of Scheme XXIV, Where Y=O, n=1)

This compound was prepared in a similar fashion as that described inExample 358, General Procedure XXI by reduction of Compound 691(Structure 119 of Scheme XXIV, where Y=O, n=1). Compound 692 wasisolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.70 (br s, 1H), 7.27(d, J=8.2, 1H), 7.18 (s, 1H), 6.80 (d, J=8.2, 1H), 6.08 (s, 1H), 4.40(br s, 1H), 2.41 to 2.36 (m, 2H), 1.94 to 1.92 (m, 2H), 1.71 (s, 6H),1.70 to 1.63 (m, 3H).

EXAMPLE 387(±)-6-(3-cis-Hydroxy)cyclohexyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 693, Structure 121 of Scheme XXIV, Where n=1)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compound 692(Structure 120 of Scheme XXIV, where Y=O, n=1). Compound 693 wasisolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.70 (br s, 1H), 7.27(d, J=8.2, 1H), 7.18 (s, 1H), 6.80 (d, J=8.2, 1H), 6.08 (s, 1H), 4.40(br s, 1H), 2.41 to 2.36 (m, 2H), 1.94 to 1.92 (m, 2H), 1.71 (s, 6H),1.70 to 1.63 (m, 3H).

EXAMPLE 388(±)-6-(3-Butyl-3-hydroxy-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-one(Compound 694, Structure 122 of Scheme XXIV, Where n=1)

To a solution of Compound 691 (Structure 119 of Scheme XXIV, where Y=O,n=1) 15 mg, 0.06 mmol) in dry THF (4 mL) at −78° C., was added a 1.6 Mn-BuLi solution in hexane (0.04 mL). After 1 h the reaction was quenchedwith saturated NH₄Cl and extracted with EtOAc (10 mL). The organic layerwas washed with brine (3×5 mL), dried (Na₂SO₄), and concentrated invacuo. The crude product was purified by PTLC (20×20 cm, 250 μm, 30%EtOAc/hex) to afford 10 mg (56%) of Compound 694 as a colorless oil: ¹HNMR (400 MHz, CDCl₃) 8.90 (br s, 1H), 7.26 (dd, J=1.7, 8.2, 1H), 7.15(d, J=1.7, 1H), 6.81 (d, J=8.2, 1H), 5.91 (s, 1H), 2.38 (m, 2H), 1.86(m, 2H), 1.80 to 1.61 (m, 10H), 1.39 (m, 4H), 0.93 (t, J=7.1, 3H).

EXAMPLE 3896-(3-Oxo-1-)Cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione(Compound 695, Structure 119 of Scheme XXIV, where Y=S, n=1)

6-Bromo-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione (Compound696, Structure 118a of Scheme XXIV):

This compound was prepared in a similar fashion as that described inExample 95, General Procedure XI from Compound 663 (Structure 114 ofScheme XXIV) as a white solid: ¹H NMR (400 MHz, CDCl₃) 10.08 (br s, 1H),7.41 (dd, J=2.0, 8.4, 1H), 7.27 (d, J=2.0, 1H), 6.81 (d, J=8.4, 1H),1.73 (s, 6H).

6-(3-Oxo-1-)Cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione(Compound 695, Structure 119 of Scheme XXIV, where Y=S, n=1):

Compound 695 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 696 and 3-ethoxy-2-cyclohexen-1-oneas a yellow solid: ¹H NMR (400 MHz, CDCl₃) 9.80 (br s, 1H), 7.50 (dd,J=1.7, 8.3, 1H), 7.34 (d, J=1.7, 1H), 6.95 (d, J=8.3, 1H), 6.42 (s, 1H),2.75 (t, J=6.3, 2H), 2.51 (t, J=6.3, 2H), 2.17 (m, 2H), 1.78 (s, 6H).

EXAMPLE 390(±)-6-(3-Hydroxy-1-)cyclohexenyl-1,4-dihydro-4,4-dimethyl-1,3-benzo[d]oxazin-2-thione(Compound 697, Structure 120 of Scheme XXIV, Where Y=S, n=1)

This compound was prepared in a similar fashion as that described inExample 358, General Procedure XXI by reduction of Compound 695(Structure 119 of Scheme XXIV, where Y=S, n=1). Compound 697 wasisolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.90 (br s, 1H), 7.31(dd, J=1.6, 8.1, 1H), 7.19 (d, J=1.6, 1H), 6.75 (d, J=8.1, 1H), 6.09 (s,1H), 4.42 (br m, 1H), 2.35 (m, 1H), 1.95 (m, 2H), 1.75 (s, 6H), 1.74 (m,2H).

EXAMPLE 391(±)-6-(1-Cyclohexenyl)-1,4-dihydro-4-methyl-1,3-benzo[d]oxazin-2-one(Compound 698, Structure 127 of Scheme XXV, Where R¹═R³=H, R²=Methyl,W=O)

(±)-1,4-Dihydro-4-methyl-1,3-benzo[d]oxazin-2-one (Compound 699,Structure 125 of Scheme XXV, Where R¹═R³=H, R²=Methyl, W=O):

To a solution of 2-tert-butoxycarbonylamino-α-methylbenzyl alcohol (0.58g, 2.4 mmol) and 1,2-dichloroethane (10 mL) was added TsOH (0.5 g, 2.6mmol) and the reaction mixture was heated to reflux. After 20 minutesthe reaction was quenched with saturated NaHCO₃ (10 mL) and extractedwith EtOAc (20 mL). The organic layer was washed with brine (3×5 mL),dried (Na₂SO₄), and concentrated in vacuo. The crude product waspurified by flash chromatography (50% EtOAc/hex) to afford 0.30 g (75%)of Compound 699 as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.64 (br s,1H), 7.27 (t, J=7.8, 1H), 7.08 (d overlapping t, 2H), 6.86 (d, J=7.8,1H), 5.50 (q, J=6.7, 1H), 1.71 (d, J=6.7, 3H).

(±)-6-Bromo-1,4-dihydro-4-methyl-1,3-benzo[d]oxazin-2-one (Compound 700,Structure 126 of Scheme XXV, where R¹═R³=H, R²=Methyl, W=O):

To a solution of Compound 699 (0.15 g, 0.64 mmol) in CCl₄ (15 mL). wasadded bromine (0.1 mL, 0.64 mmol). Stirred at room temperature for 1 hr.The reaction mixture was concentrated in vacuo to afford an orangesolid. Washed solid with hot hexane and filtered to afford 130 mg (84%)of Compound 700 as a tan solid: ¹H NMR (400 MHz, CDCl₃) 7.74 (br s, 1H),7.37 (dd, J=1.7, 8.5, 1H), 7.25 (d under solvent peak, 1H), 6.70 (d,J=8.5, 1H), 5.45 (q, J=6.6, 1H), 1.70 (d, J=6.6, 1H).

(±)-6-(1-Cyclohexenyl)-1,4-dihydro-4-methyl-1,3-benzo[d]oxazin-2-one(Compound 698, Structure 127 of Scheme XXV, Where R¹═R³=H, R²=Methyl,W=O):

Compound 527 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 700 and cyclohexanone as a whitesolid: ¹H NMR (400 MHz, CDCl₃) 8.60 (br s, 1H), 7.26 (dd under solventpeak, 1H), 7.09 (d, J=1.7, 1H), 6.78 (d, J=8.2, 1H), 6.07 (m, 1H), 5.50(q, J=6.7, 1H), 2.38 (m, 2H), 2.19 (m, 1H), 1.78 (m, 2H), 1.71 (d,J=6.7, 3H), 1.67 (m, 2H).

EXAMPLE 3926-(1-Cyclohexenyl)-1,4-dihydro-4,4,5-trimethyl-1,3-benzo[d]oxazin-2-one(Compound 701, Structure 127 of Scheme XXV, Where R¹═R²═R³=Methyl W=O)

2-(1-Hydroxyisopropyl)-3-methylaniline (Compound 702, Structure 124 ofScheme XXV, Where R¹═R²═R²=Methyl):

To a solution of 2-amino-6-methylbenzoic acid (Structure 123 of SchemeXXV, where R²=methyl) (0.50 g, 3.3 mmol) and dry THF (20 mL) was added 3M MeMgCl in THF (11 mL) at 0° C. The reaction was heated to 50° C. andstirred for 15 hrs. The reaction mixture was cooled to room temperaturethen poured into saturated NH₄Cl (20 mL) and extracted with EtOAc (20mL). The organic layer was washed with brine (3×5 mL), dried (Na₂SO₄),and concentrated in vacuo. The crude product was purified by flashchromatography (100% hexane to 50% EtOAc/hex gradient) to afford 0.36 g(65%) of Compound 702 as a light orange oil: ¹H NMR (400 MHz, CDCl₃)6.89 (t, J=7.7, 1H), 6.52 (d under d, J=7.7, 2H), 2.40 (s, 3H), 1.75 (s,6H).

1,4-Dihydro-4,4,5-trimethyl-1,3-benzo[d]oxazin-2-one (Compound 703,Structure 125 of Scheme XXV, Where R¹═R²═R²=Methyl, W=O):

To a solution of Compound 702 (0.36 g, 2.2 mmol) and dry THF (10 mL) wasadded DMAP (0.29 g, 2.4 mmol) and 1,1′-carbonyldiimidazole (0.39 g, 2.4mmol). The reaction mixture was heated to 50° C. for 1.5 hrs. Thereaction mixture was cooled to room temperature then poured intosaturated NH₄Cl (20 mL) and extracted with EtOAc (20 mL). The organiclayer was washed with brine (3×5 mL), dried (Na₂SO₄), and concentratedin vacuo. The crude product was purified by flash chromatography (50%EtOAc/hex) to afford 0.40 g (95%) of Compound 703 as a white solid: ¹HNMR (400 MHz, CDCl₃) 7.97 (br s, 1H), 7.10 (t, J=7.8, 1H), 6.85 (d,J=7.8, 1H), 6.64 (d, J=7.8, 1H), 2.41 (s, 3H), 1.80 (s, 6H).

6-Bromo-1,4-dihydro-4,4,5-trimethyl-1,3-benzo[d]oxazin-2-one (Compound704, Structure 126 of Scheme XXV, where R¹═R²═R³=methyl, W═O):

To a solution of Compound 703 (100 mg, 0.52 mmol) and CCl₄ (5 mL) wasadded bromine (0.05 mL, 1.0 mmol). Stirred at room temperature for 1.0hr. The reaction mixture was concentrated in vacuo to afford an orangesolid. Washed solid with hot hexane and filtered to afford 140 mg (100%)of Compound 704 as a tan solid: ¹H NMR (400 MHz, CDCl₃) 8.18 (br s, 1H),7.44 (d, J=8.5, 1H), 6.54 (d, J=8.5, 1H), 2.49 (s, 3H), 1.83 (s, 6H).

6-(1-Cyclohexenyl)-1,4-dihydro-4,4,5-trimethyl-1,3-benzo[d]oxazin-2-one(Compound 701, Structure 127 of Scheme XXV, where R¹═R²═R³=methyl, W═O):

Compound 701 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 704 and cyclohexanone as a whitesolid: ¹H NMR (400 MHz, CDCl₃) 7.52 (br s, 1H), 6.94 (d, J=8.0, 1H),6.55 (d, J=8.0, 1H), 5.52 (m, 1H), 2.29 (s, 3H), 2.16 to 2.11 (m, 4H),1.18 (s, 6H), 1.75 to 1.67 (m, 4H).

EXAMPLE 3936-(1-Cyclohexenyl)-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound705, Structure 127 of Scheme XXV, Where R¹═R²=Methyl, R³=H, W=Methylene)

6-Bromo-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound 706,Structure 126 of Scheme XXV, Where R¹═R²=Methyl, R³=H, W=Methylene):

To a solution of Compound 504 (Structure 125 of Scheme XXV, whereR¹═R²=methyl, R³=H, W=methylene) (0.20 g, 1.1 mmol) and CCl₄ (20 mL) wasadded bromine (0.05 mL, 1.1 mmol). Stirred at room temperature for 1.5hrs. The reaction mixture was concentrated in vacuo to afford an orangesolid. Washed solid with hot hexane and filtered to afford 0.20 g ofCompound 706 in 67% yield as a light orange solid: ¹H NMR (400 MHz,CDCl₃) 8.40 (br s, 1H), 7.41 (d, J=2.1, 1H), 7.31 (dd, J=2.1, 8.4, 1H),6.72 (d, J=8.4, 1H), 2.50 (s, 2H), 1.33 (s, 6H).

6-(1-Cyclohexenyl)-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone (Compound705, Structure 127 of Scheme XXV, Where R¹═R²=Methyl, R³=H,W=Methylene):

Compound 705 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 706 and cyclohexanone as a whitesolid: ¹H NMR (400 MHz, CDCl₃) 8.05 (br s, 1H), 7.31 (d, J=1.8, 1H),7.18 (dd, J=1.8, 8.3, 1H), 6.71 (d, J=8.3, 1H), 6.07 (td, J=2.3, J=4.1,1H), 2.48 (s, 2H), 2.39 (m, 2H), 2.20 (m, 2H), 1.78 (m, 2H), 1.66 (m,2H), 1.34 (s, 6H).

EXAMPLE 394 6-Cyclohexyl-3,4-dihydro-4,4-dimethyl-2(1H)-quinolinone(Compound 707, Structure 128 of Scheme XXV)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compound 705(Structure 127 of Scheme XXV, where R¹═R²=methyl, R³=H, W=methylene).Compound 707 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 8.03(br s, 1H), 7.11 (d, J=1.5, 1H), 7.01 (dd, J=1.5, J=8.0, 1H), 6.69 (d,J=8.0, 1H), 2.47 (s, 2H), 1.87 to 1.74 (m, 4H), 1.42 to 1.26 (m, 13H).

EXAMPLE 395(±)-8-Bromo-6-(1-cyclohexenyl)-1,4-dihydro-4-trifluoromethyl-1,3-benzo[d]oxazin-2-one(Compound 708, Structure 132 of Scheme XXVI)

(±)-N-tert-Butoxycarbonyl-2-(1-hydroxy-2,2,2-trifluoroethyl)aniline(Compound 709, Structure 129 of Scheme XXVI):

To a solution of N-tert-Boc-2-bromoaniline (1.0 mL, 3.8 mmol) in dryEt₂O/THF (1:1, 10 mL) was added 1.4 M MeLi/Et₂O (3.3 mL) at roomtemperature. After 15 min. the white turbid mixture was cannulated intoa flask charged with 1.7 M t-BuLi/pentane (5 mL) and dry Et₂O/THF (1:1,10 mL) at −78° C. Stirred at −78° C. for 1 hr then addedethyltrifluoroacetate (2.5 mL, 21 mmol, freshly distilled). Allowedreaction to slowly warm to rt overnight. Quenched with saturated NH₄Cland extracted with EtOAc. Washed organic layer with brine, dried(Na₂SO₄) and concentrated in vacuo to afford a yellow oil. Purified byflash chromatography (hex to 25% EtOAc/hex) to give the desired2-N-Boc-aminotriflouroacetophenone (0.28 g) as a white solid: ¹H NMR(400 MHz, CDCl₃) 8.13 (d, J=7.4, 1H), 7.38 (dd, J=1.5, 7.4, 1H), 7.28(t, J=7.4, 1H), 6.99 (br s, 1H), 6.91 (dt, J=1.5, 7.4, 1H), 1.52 (m,9H). The trifluoroacetophenone was treated with NaBH₄ in methanolfollowed by standard work-up to afford Compound 709 as a white solid: ¹HNMR (400 MHz, CDCl₃) 7.76 (d, J=7.9, 1H), 7.38 (m, 2H), 7.14 (t, J=7.9,1H), 5.15 (m, 1H), 3.34 (d, J=4,4, 1H), 1.51 (m, 9H).

(±)-1,4-Dihydro-4-trifluoromethyl-1,3-benzo[d]oxazin-2-one (Compound710, Structure 130 of Scheme XXVI):

To a solution of Compound 709 (0.24 g, 0.82 mmol) in dichloromethane (15mL) was added TsOH (160 mg). Heated to reflux for 1.5 hr. Quenched withsaturated NaHCO₃. Extracted with EtOAc, washed organic layer with brine,dried (Na₂SO₄) and concentrated in vacuo to afford 150 mg of Compound710 as a white solid (84%): ¹H NMR (400 MHz, CDCl₃) 7.23 (m, 2H), 6.87(t, J=7.7, 1H), 6.78 (d, J=7.7, 1H), 5.07 (q, J=7.4, 1H).

(±)-6,8-Dibromo-1,4-dihydro-4-trifluoromethyl-1,3-benzo[d]oxazin-2-one(Compound 711, Structure 131 of Scheme XXVI):

To a solution of Compound 710 (50 mg, 0.23 mmol) and CCl₄ (5 mL) wasadded bromine (0.01 mL, 0.23 mmol) at room temperature. After 1 hr thereaction was concentrated in vacuo to afford a yellow foamy solid.Washed solid with hexane to afford 35 mg (41%) of Compound 711 as asolid: ¹H NMR (400 MHz, CDCl₃) 7.35 (s, 1H), 7.29 (dd, J=2.4, 8.5, 1H),6.64 (d, J=8.5, 1H), 5.04 (q, J=7.0, 1H), 4.00 (br s, 1H).

(±)-8-Bromo-6-(1-cyclohexenyl)-1,4-dihydro-4-trifluoromethyl-1,3-benzo[d]oxazin-2-one(Compound 708, Structure 132 of Scheme XXVI):

Compound 537 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 711 and cyclohexanone as a whitesolid: ¹H NMR (400 MHz, CDCl₃) 7.52 (d, J=2.0, 1H), 7.19 (d, J=2.0, 1H),6.01 (m, 1H), 5.08 (m, 1H), 4.50 (br s, 1H), 2.31 (m, 2H), 2.17 (m, 2H),1.76 (m, 2H), 1.64 (m, 2H).

EXAMPLE 396 5-(3-oxo-1-)Cyclohexenyl-3,3-dimethyl-2-indolone (Compound712, Structure 134 of Scheme XXVII, Where R¹═R²=Methyl, R³R⁴=Carbonyl,n=2)

5-Bromo-3,3-dimethyl-2-indolone (Compound 713, Structure 133 of SchemeXXVII, Where R¹R²=Methyl):

This compound was prepared by the following General Procedure XXII(Alkylation and bromination of 2-indolone):

To a solution of 2-indolone (200 mg, 1.5 mmol) in dry THF (15 mL) andTMEDA (0.45 mL, 3.0 mmol) at −78° C. was added n-BuLi (1.9 mL, 1.6M inhex.). The reaction mixture was warmed to −20° C. and iodomethane wasadded (0.1 mL, 1.5 mmol). After 1 hr, added another equivalent ofiodomethane (0.1 mL, 1.5 mmol). Warmed reaction mixture to roomtemperature and stirred for 15 hrs. Quenched reaction with saturatedNH₄Cl (10 mL) and extracted with EtOAc (20 mL). The organic layer waswashed with brine (3×10 mL), dried (Na₂SO₄), and concentrated in vacuo.Purified by flash chromatography (10% hexane/EtOAc to 50% hexane/EtOAcgradient) to afford 126 mg (52%) of 3,3-dimethyl-2-indolone as a whitesolid. Next, to a solution of the 3,3-dimethyl-2-indolone (126 mg, 0.78mmol) and CCl4 (10 mL) was added bromine (0.04 mL, 0.78 mmol) at roomtemperature. After 1 hr, the reaction mixture was partitioned betweenEtOAc (10 mL) and brine (5 mL). The organic layer was washed with brine(3×5 mL), dried (Na₂SO₄), and concentrated in vacuo to afford 180 mg(96%) of Compound 713 as a white solid: ¹H NMR (400 MHz, CDCl₃) 9.00 (brs, 1H), 7.38 (d, J=8.2, 1H), 7.35 (s, 1H), 6.97 (d, J=8.2, 1H), 1.44 (s,6H).

5-(3-oxo-1-)Cyclohexenyl-3,3-dimethyl-2-indolone (Compound 712,Structure 134 of Scheme XXVII, Where R¹═R²=Methyl, R³R⁴=Carbonyl, n=2):

Compound 712 was made according to General Procedures XIX and XX inExamples 330 and 331 from Compound 713 and 3-ethoxy-2-cyclohexen-1-oneas a white solid: ¹H NMR (400 MHz, CDCl₃) 9.45 (br s, 1H), 7.45 (d underdd, 2H), 7.02 (d, J=8.0, 1H), 6.44 (s, 1H), 2.79 (t, J=6.1, 2H), 2.50(t, J=6.1, 2H), 2.17 (m, 2H), 1.44 (s, 6H).

EXAMPLE 397 (±)-5-(3-Hydroxy-1-)cyclohexenyl-3,3-dimethyl-2-indolone(Compound 714, Structure 135 of Scheme XXVII, n=2)

This compound was prepared in a similar fashion as that described inExample 358, General Procedure XXI by reduction of Compound 712(Structure 134 of Scheme XXVII, where R¹═R²=methyl, R³R⁴=carbonyl, n=2).Compound 714 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.96(br s, 1H), 7.24 (d under dd, 2H), 6.09 (br d, 1H), 4.41 (br s, 1H),2.39 (m, 2H), 1.93 (m, 2H), 1.76 to 1.58 (m, 3H), 1.40 (s, 6H).

EXAMPLE 398 (±)-5-(3-Oxocyclohexyl)-3,3-dimethyl-2-indolone (Compound715, Structure 136 of Scheme XXVII, Where R¹═R²=Methyl, R³R⁴=Carbonyl,n=2)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure III by hydrogenation of Compound 712(Structure 134 of Scheme XXVII, where R¹═R²=methyl, R³R⁴=carbonyl, n=2).Compound 715 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.03(d under dd, 2H), 6.78 (d, J=8.5, 1H), 2.49 (m, 1H), 1.86 (m, 3H), 1.81(m, 1H), 1.39 to 1.25 (m, 10H).

EXAMPLE 399 5-Cyclohexyl-3,3-spirocyclohexyl-2-indolone (Compound 716,Structure 136 of Scheme XXVII, Where R¹R²=Spirocyclohexyl, R³═R⁴=H, n=2)

5-Bromo-3,3-spirocyclohexyl-2-indolone (Compound 717, Structure 133 ofScheme XXVII, Where R¹R²=Spirocyclohexyl):

This compound was prepared in a similar fashion as that described inExample 396, General Procedure XXII but using 1,5-diiodopentane in placeof iodomethane. Compound 717 was isolated as a white solid: ¹H NMR (400MHz, CDCl₃) 7.98 (bs, 1H), 7.54 (s, 1H), 7.33 (dd, J=1.2, 8.2, 1H), 6.78(d, 8.2, 1H), 1.94-1.58 (m, 10H).

5-Cyclohexyl-3,3-spirocyclohexyl-2-indolone (Compound 716, Structure 136of Scheme XXVII, Where R¹R²=Spirocyclohexyl, R³═R⁴=H, n=2):

Compound 716 was made according to General Procedures XIX, XX and III inExamples 330, 331 and 1 from Compound 717 and cyclohexanone as a whitesolid: ¹H NMR (400 MHz, CDCl₃) 7.97 (bs, 1H), 7.27 (s, 1H), 7.04 (dd,J=1.1, 7.8, 1H), 6.81 (d, J=7.9, 1H), 2.48 (m, 1H), 1.94-1.65 (mm, 18H),1.43-1.37 (m, 4H).

EXAMPLE 400 5-Cyclopentyl-3,3-spirocyclohexyl-2-indolone (Compound 718,Structure 136 of Scheme XXVII, Where R¹R²=Spirocyclohexyl, R³═R⁴=H, n=1)

Compound 718 was made according to General Procedures XIX, XX and III inExamples 330, 331 and 1 from Compound 717 (Structure 133 of SchemeXXVII, where R¹R²=spirocyclohexyl) and cyclopentanone as a white solid:¹H NMR (400 MHz, CDCl₃) 8.42 (bs, 1H), 7.31 (s, 1H), 7.08 (dd, J=1.0,8.1, 1H), 6.83 (d, J=8.0, 1H), 2.97 (quint., J=7.5, 1H), 2.06 (m, 2H),1.94 (m, 2H), 1.89-1.63 (m, 14H).

EXAMPLE 401 6-(1-Hydroxycyclohexyl)-2(3H)-benzothiozolone (Compound 719,Structure 138 of Scheme XXVIII)

Compound 719 was made according to General Procedures XIX in Examples330 from 6-bromo-2(3H)-benzothiozolone (Structure 137 of Scheme XXVIII)(120 mg, 0.52 mmol) and cyclohexanone (0.11 mL, 1.04 mmol) in 87% yield(113 mg) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) 11.77 (bs, 1H),7.63 (d, J=1.5, 1H), 7.38 (dd, J=8.4, 1.5, 1H), 7.03 (d, J=8.4, 1H),4.70 (s, 1H), 1.64 (m, 8H), 1.48 (m, 2H).

EXAMPLE 402 6-Cyclohexenyl-2(3H)-benzothiozolone (Compound 720,Structure 139 of Scheme XXVIII)

Compound 720 was made according to General Procedures XX in Examples 331by dehydration of Compound 719 (Structure 138 of Scheme XXVIII) as awhite solid: ¹H NMR (400 MHz, CDCl₃) 9.38 (s, 1H), 7.40 (d, J=1.5, 1H,7.29 (dd, J=8.4, 1.8, 1H), 7.05 (d, J=8.4, 1H), 6.07 (bt, J=4.0, 1H),2.39-2.36 (m, 2H), 2.21-2.18 (m, 2H), 1.81-1.75 (m, 2H), 1.68-1.63 (m,2H).

EXAMPLE 403 3,4-Dihydro-6-isopropyl-3-methyl-2(1H)-quinazolinone(Compound 721, Structure 143 of Scheme XXIX, Where R=H, R¹═R²=Methyl)

6-Bromo-3,4-dihydro-3-methyl-2(1H)-quinazolinone (Compound 722,Structure 141 of Scheme XXIX):

In a 100-mL r.b. flask, a solution of commercially available3,4-dihydro-3-methyl-2(1H)-quinazolinone (Structure 140 of Scheme XXIX)(1.0 g, 6.2 mmol) in CH₂Cl₂ (30 mL) was treated with NBS (1.2 g, 6.8mmol, 1.1 equiv) in portions. The reaction mixture was then allowed tostir at room temperature for 2 h, diluted with CH₂Cl₂ (125 mL), washedwith water (2×30 mL), Brine (30 mL), dried (MgSO₄), filtered andconcentrated under reduced pressure to yield 1.5 g (99%) of Compound 722as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.26 (m, 1H), 7.16 (s, 1H),6.57 (d, J=8.4, 1H), 4.41 (s, 2H), 3.02 (s, 3H).

3,4-Dihydro-6-isopropyl-3-methyl-2(1H)-quinazolinone (Compound 721,Structure 143 of Scheme XXIX, Where R=H, R¹═R²=Methyl):

In a 25-mL r.b. flask,dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (4 mg, 0.01-0.02 equiv) was flame-dried under astream of N₂. The flask was them cooled to −70° C. where a solution ofisopropyl magnesium chloride (2 M in THF) (0.62 mL, 3.0 equiv) was addedfollowed by the addition of Compound 551 (100 mg, 0.41 mmol) in THF (2mL). The reaction mixture was then allowed to warm to room temperature,stirred overnight, quenched with HCl (1 M, 5 mL), diluted with water (5mL), and extracted with EtOAc (3×30 mL). The combined organic layerswere then washed with water (15 mL), Brine (20 mL), dried (MgSO₄),filtered, and concentrated to give crude product. Compound 721 (5 mg,6%) was isolated by reverse phase HPLC (ODS, 70% MeOH/water, 2.5mL/min). Data for Compound 721: ¹H NMR (400 MHz, CDCl₃) 7.01 (d, J=8.3,1H), 6.89 (s, 1H), 6.74 (bs, 1H), 6.58 (d, J=8.1, 1H), 4,43 (s, 2H),3.02 (s, 3H), 2.83 (m, 1H), 1.21 (d, J=6.9, 6H).

EXAMPLE 404 1-Benzyl-6-bromo-3,4-dihydro-3-methyl-2(1H)-quinazolinone(Compound 723, Structure 142 of Scheme XXIX)

This compound was prepared in a similar fashion as that described inExample 92, General Procedure X from Compound 722 (Structure 141 ofScheme XXIX) and benzyl bromide. Compound 723 was isolated as a whitesolid: ¹H NMR (400 MHz, CDCl₃) 7.29 (m, 2H), 7.21 (m, 3H), 7.17 (m, 2H),6.55 (d, J=9.2, 1H), 5.09 (s, 2H), 4,42 (s, 2H), 3.08 (s, 3H).

EXAMPLE 4051-Benzyl-6-cyclohexyl-3,4-dihydro-3-methyl-2(1H)-quinazolinone (Compound724, Structure 143 of Scheme XXIX, R¹R²=Cyclohexyl, R=Benzyl)

Compound 724 was made according to General Procedures XIX, XX and III inExamples 330, 331 and 1 from Compound 723 (Structure 142 of Scheme XXIX)and cyclohexanone as a white solid: ¹H NMR (400 MHz, CDCl₃) 7.26 (mm,5H), 6.92 (d, J=8.5, 1H), 6.88 (s, 1H), 6.62 (d, J=8.4, 1H), 5.10 (s,2H), 4,44 (s, 2H), 3.09 (s, 3H), 2.37 (m, 1H), 1.80 (m, 4H), 1.74-1.66(m, 2H), 1.37-1.27 (m, 4H).

EXAMPLE 406 6-(2,3-Difluoro)phenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 725, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=2,3-Difluorine)

2,3-Difluoro-benzeneboronic Acid (Compound 726, Structure 144 of SchemeXXX, Where R²=2,3-Difluoro):

General Procedure XXIII (Boronic acid formation):

To a solution of an aryl bromide (0.5-1.0 M THF) cooled to −70° C. underan N₂ atmosphere was added n-BuLi (1.1 equiv) via syringe pump. The rateof addition is adjusted so that the internal temperature did not riseabove −65° C. After complete addition of n-BuLi the reaction mixture wasallowed to stir at −70° C. for 3 h before quenching with dry trimethylborate (3.0 equiv), again adjusting the rate so that the internaltemperature did not rise above −65° C. After complete addition oftrimethyl borate the reaction mixture was then slowly warmed to roomtemperature overnight. The thick reaction mixture was then acidified topH 2 with an HCl solution, extracted with EtOAc (20 mL/mmol), washedwith brine (2 mL/mmol), dried (MgSO₄), filtered and concentrated. Thecrude product was then triturated with hexanes to give the desiredboronic acid in quantitative yield.

Compound 726 was prepared according to General Procedure XXIII from1,2-difluorobenzene (20 g, 0.18 mmol), n-BuLi (8.2 M in hexane, 21.4 mL,0.18 mmol), and trimethyl borate (60 mL, 0.53 mmol) in quantitativeyield. Compound 726 was isolated as a white solid: ¹H NMR (400 MHz,CDCl₃) 7.56 (m, 1H), 7.28 (m, 1H), 7.15 (mm, 1H), 5.05 (d, J=5.6, 2H).

6-(2,3-Difluoro)phenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound725, Structure 145 of Scheme XXX, Where R=H, R¹=Trifluoromethyl,R²=2,3-Difluorine):

General Procedure XXIV (Suzuki coupling of 6-bromoquinolinones to arylboronic acids):

To a 10-mL flask charged with a solution of a 6-bromo-2(1H)-quinolinone(25 mg, 0.09 mmol, 1 equiv) in DME (0.1 M) was sequentially addedtetrakis(triphenylphosphine)-palladium (0.02-0.05 equiv), aryl boronicacid (R²B(OH)₂) (1.5 equiv, 0.1 M in ethanol), and K₂CO₃ (2.0 equiv, 2.0M). The yellow reaction mixture was heated to reflux overnight. The nowclear reaction solution was cooled, diluted with EtOAc, washed withwater (2×15 mL), Brine (20 mL), dried (MgSO₄), filtered and concentratedunder reduced pressure. The crude product was then purified bytrituration with EtOAc/hexane (15%) followed by recrystallization fromMeOH/EtOAc to yield the desired product as a white solid in 40-80%overall yield.

Compound 725 was made according to General Procedure XXIV from Compound308 (Structure 16c of Scheme XXX, where R=H, R¹=trilfuoromethyl) andCompound 726 as a white solid: ¹H NMR (400 MHz, CDCl₃) 12.46 (bs, 1H),8.00 (s, 1H), 7.81 (d, J=8.6, 1H), 7.57 (d, J=8.6, 1H), 7.21 (m, 3H),7.16 (s, 1H).

EXAMPLE 407 4-Trifluoromethyl-6-(3-nitro)phenyl-2(1H)-quinolinone(Compound 727, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3-Nitro)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 3-nitrobenzeneboronicacid. Compound 727 was isolated as a white solid: ¹H NMR (400 MHz,CDCl₃) 12.02 (bs, 1H), 8.45 (d, J=2.0, 1H), 8.26 (dd, J=8.0, 2.3, 1H),8.04 (s, 1H), 7.93 (d, J=7.7, 1H), 7.88 (d, J=8.3, 1H), 7.68 (t, J=7.9,1H), 7.19 (s, 1H).

EXAMPLE 408 4-Trifluoromethyl-6-(3,5-dichloro)phenyl-2(1H)-quinolinone(Compound 728, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3,5-Dichloro)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available2,3-dichlorobenzeneboronic acid. Compound 728 was isolated as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) 12.46 (s, 1H), 8.02 (dd, J=8.7, 1.5,1H), 7.82 (s, 1H), 7.69 (d, J=1.7, 2H), 7.65 (d, J=1.8, 1H), 7.54 (d,J=8.6, 1H), 7.07 (s, 1H).

EXAMPLE 4094-Trifluoromethyl-6-(3-fluoro-5-N-hydroxyliminomethyl)phenyl-2(1H)-quinolinone(Compound 729, Structure 146 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R³=3-Fluoro-5-(N-hydroxyliminomethyl)

4-Trifluoromethyl-6-(3-fluoro-5-formylmethylphenyl)-2(1H)-quinolinone(Compound 730, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3-Fluoro-5-formyl):

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) (500 mg, 1.70 mmol) and3-fluoro-5-formylbenzeneboronic acid (350 mg, 2.55 mmol, 1.5 equiv). Thecrude product could not be purified and was used directly in thefollowing step.

4-Trifluoromethyl-6-(3-fluoro-5-(N-hydroxylimino)methylphenyl)-2(1H)-quinolinone(Compound 729, Structure 146 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R³=3-Fluoro-5-(N-hydroxyliminomethyl):

The crude Compound 730 was dissolved in EtOH and treated withhydroxylamine-hydrochloride salt (180 mg, 2.55 mmol, 1.5 equiv) andpyridine (0.2 mL, 2.55 mmol, 1.5 equiv) at room temperature overnight.The crude product was then concentrated, dissolved in EtOAc (200 mL),washed with sat. NH₄Cl (10 mL), water (10 mL), Brine (10 mL), dried(MgSO₄), filtered and concentrated. The crude product was thenrecrystallized from MeOH/EtOAc to afford desired Compound 729 as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) 12.45 (bs, 1H), 11.54 (s, 1H), 8.27 (s,1H), 8.01 (dd, J=7.0, 1.7, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.55 (d,J=8.4, 1H), 7.53 (dd, J=11.2, 1.5, 1H), 7.43 (dd, J=9.8, 1.5, 1H), 7.06(s, 1H).

EXAMPLE 4104-Trifluoromethyl-6-(3-fluoro-5-cyano)phenyl-2(1H-quinolinone (Compound731, Structure 146 of Scheme XXX, Where R=H, R¹=Trifluoromethyl,R³=3-Fluoro-5-cyano)

In a 25 mL flask, a solution of Compound 729 (Structure 145 of SchemeXXX, where R=H, R¹=trifluoromethyl,R²=3-fluoro-5-(N-hydroxyliminomethyl) in methylene chloride was treatedwith thionyl chloride (1.1 equiv) at room temperature for 30 min. tillthe reaction went completion by TLC. The reaction was quenched withK₂CO₃ and extracted with EtOAc. Removal of solvent and chromatographyafforded Compound 731 as a white solid: ¹H NMR (400 MHz, DMSO-d₆) 12.49(s, 1H), 8.06 (m, 2H), 7.93 (dd, J=10.1, 1.5, 1H), 7.89 (m, 2H), 7.55(d, J=8.7, 1H), 7.08 (s, 1H).

EXAMPLE 4114-Trifluoromethyl-6-(3-fluoro-5-chloro)phenyl-2(1H)-quinolinone(Compound 732, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3-Fluoro-5-chloro)

3-Chloro-5-fluorobenzeneboronic Acid (Compound 733, Structure 144 ofScheme XXX, Where R²=3-Fluoro-5-chloro):

This compound was prepared according to General Procedure XXIII inExample 406 from 1-bromo-3-chloro-5-fluorobenzene (20 g, 0.18 mmol),n-BuLi (8.2 M in hexane, 21 mL, 0.18 mmol), and trimethyl borate (60 mL,0.53 mmol) to give 2,3-difluoro-benzeneboronic acid as a white solid.

4-Trifluoromethyl-6-(3-fluoro-5-chloro)phenyl-2(1H)-quinolinone(Compound 732, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3-Fluoro-5-chloro):

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and Compound 733. Compound 732 was isolated as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) 12.45 (s, 1H), 8.03 (d, J=8.7,1H), 7.58-7.52 (m, 3H), 7.48 (d, J=8.7, 1H), 7.07 (s, 1H).

EXAMPLE 4124-Trifluoromethyl-6-(4-hydroxymethyl)phenyl-2(1H)-quinolinone (Compound734, Structure 145 of Scheme XXX, Where R=H, R¹=Trifluoromethyl,R²=4-Hydroxymethyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available4-hydroxymethylbenzeneboronic acid. Compound 734 was isolated as a whitesolid: ¹H NMR (400 MHz, CDCl₃) 12.43 (s, 1H), 7.97 (d, J=8.5, 1H), 7.82(s, 1H), 7.61 (d, J=8.1, 2H), 7.54 (d, J=8.6, 1H), 7.44 (d, J=8.1, 2H),7.04 (s, 1H), 5.26 (bs, 1H), 4.56 (d, J=5.0, 2H).

EXAMPLE 413 4-Trifluoromethyl-6-(3-acetylphenyl)-2(1H)-quinolinone(Compound 735, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3-Acetyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 3-acetylbenzeneboronicacid. Compound 735 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.45 (s, 1H), 8.15 (s, 1H), 8.04 (d, J=8.8, 1H), 8.00 (d,J=7.8, 1H), 7.91 (d, J=8.0, 1H), 7.86 (s, 1H), 7.67 (t, J=7.7, 1H), 7.58(d, J=8.6, 1H), 7.06 (s, 1H), 2.66 (s, 3H).

EXAMPLE 414 4-Trifluoromethyl-6-(4-ethylphenyl)-2(1H)-quinolinone(Compound 736, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=4-ethyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 4-ethylbenzeneboronicacid. Compound 736 was isolated as a white solid: ¹H NMR (400 MHz,CDCl₃) 11.78 (bs, 1H), 8.00 (s, 1H), 7.84 (d, J=8.6, 1H), 7.53 (d,J=8.0, 2H), 7.48 (d, J=8.6, 1H), 7.32 (d, J=8.0, 2H), 7.13 (s, 1H), 2.72(q, J=7.5, 2H), 1.29 (t, J=7.6, 3H).

EXAMPLE 415 4-Trifluoromethyl-6-(3-ethoxylphenyl)-2(1H)-quinolinone(Compound 737, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3-Ethoxyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 3-methoxybenzeneboronicacid. Compound 737 was isolated as a white solid: ¹H NMR (400 MHz,CDCl₃) 12.25 (bs, 1H), 8.02 (s, 1H), 7.84 (d, J=8.5, 1H), 7.53 (d,J=8.6, 1H), 7.41 (t, J=8.0, 1H), 7.19 (d, J=6.5, 1H), 7.14 (m, 2H), 6.95(d, J=8.3, 1H), 3.89 (s, 3H).

EXAMPLE 416 4-Trifluoromethyl-6-(3-methylphenyl)-2(1H)-quinolinone(Compound 738, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3-Methyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 3-methylbenzeneboronicacid. Compound 738 was isolated as a white solid: ¹H NMR (400 MHz,CDCl₃) 12.38 (bs, 1H), 8.01 (s, 1H), 7.84 (d, J=8.6, 1H), 7.54 (d,J=8.5, 1H), 7.38 (m, 3H), 7.22 (d, J=6.8, 1H), 7.15 (s, 1H), 2.46 (s,3H).

EXAMPLE 4174-Trifluoromethyl-6-(3-trifluoromethylphenyl)-2(1H)-quinolinone(Compound 739, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3-Trifluoromethyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available3-trifluoromethylbenzeneboronic acid. Compound 739 was isolated as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) 12.46 (bs, 1H), 8.06 (d, J=8.6,1H), 7.97 (d, J=6.8, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.75 (m, 2H), 7.57(8.7, 1H), 7.07 (s, 1H).

EXAMPLE 418 4-Trifluoromethyl-6-(3-chlorophenyl)-2(1H)-quinolinone(Compound 740, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3-Chloro)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 3-chlorobenzeneboronicacid. Compound 740 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.46 (s, 1H), 8.01 (d, J=7.0, 1H), 7.82 (s, 1H), 7.71 (s, 1H),7.62 (d, J=7.7, 1H), 7.56-7.47 (m, 3H), 7.07 (s, 1H).

EXAMPLE 419 4-Trifluoromethyl-6-(3-fluorophenyl)-2(1H)-quinolinone(Compound 741, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3-Fluoro)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 3-fluorobenzeneboronicacid. Compound 741 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.46 (s, 1H), 8.00 (dd, J=8.5, 1.8, 1H), 7.84 (s, 1H),7.68-7.49 (m, 4H), 7.24 (t, J=9.3, 1H), 7.06 (s, 1H).

EXAMPLE 420 4-Trifluoromethyl-6-(2-methylphenyl)-2(1H)-quinolinone(Compound 742, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=2-Methyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 2-methylbenzeneboronicacid. Compound 742 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.42 (s, 1H), 7.68 (dd, J=9.6, 1.4, 1H), 7.53 (m, 2H),7.33-7.23 (m, 4H), 7.04 (s, 1H), 2.51 (s, 3H).

EXAMPLE 421 4-Trifluoromethyl-6-(4-formyl)phenyl-2(1H)-quinolinone(Compound 743, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=4-Formyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 4-formylbenzeneboronicacid. Compound 743 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.49 (s, 1H), 10.08 (s, 1H), 8.08 (d, J=10.3, 1H), 8.04 (d,J=8.2, 2H), 7.92 (s, 1H), 7.91 (d, J=8.2, 2H), 7.58 (d, J=8.6, 1H), 7.07(s, 1H).

EXAMPLE 422 4-Trifluoromethyl-6-(4-tert-butylphenyl)-2(1H)-quinolinone(Compound 744, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=4-tert-Butyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available4-tert-butylbenzeneboronic acid. Compound 744 was isolated as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) 12.40 (s, 1H), 7.95 (d, J=7.8, 1H),7.81 (s, 1H), 7.58-7.51 (m, 4H), 7.04 (s, 1H), 1.32 (s, 9H).

EXAMPLE 423 4-Trifluoromethyl-6-(2-methylphenyl)-2(1H)-quinolinone(Compound 745, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=2-Methoxy)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H, R¹trilfuoromethyl) and commercially available 2-methoxybenzeneboronicacid. Compound 745 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.38 (s, 1H), 7.81 (s, 1H), 7.77 (dd, J=8.6, 1.4, 1H), 7.49(d, J=8.4, 1H), 7.38 (dt, J=8.3,1.7, 1H), 7.34 (dd, J=7.9, 1.5, 1H),7.15 (d, J=8.1, 1H), 7.07 (t, J=7.5, 1H), 7.02 (s, 1H), 3.78 (s, 3H).

EXAMPLE 424 4-Trifluoromethyl-6-(2-fluorophenyl)-2(1H)-quinolinone(Compound 746, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=2-Fluoro)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 2-fluorobenzeneboronicacid. Compound 746 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.42 (bs, 1H), 7.85 (d, J=8.8, 1H), 7.81 (s, 1H), 7.55 (m,2H), 7.45 (m, 1H), 7.35 (m, 2H), 7.04 (s, 1H).

EXAMPLE 425 4-Trifluoromethyl-6-(4-acetylphenyl)-2(1H)-quinolinone(Compound 747, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=4-Acetyl)

This compound was made according to General, Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 4-acetylbenzeneboronicacid. Compound 747 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.06 (bs, 1H), 8.06 (m, 3H), 7.87 (dd, J=8.7, 1.5, 1H), 7.69(d, J=8.4, 2H), 7.55 (d, J=8.6, 1H), 7.15 (s, 1H), 2.65 (s, 3H).

EXAMPLE 426 4-Trifluoromethyl-6-(4-methylphenyl)-2(1H)-quinolinone(Compound 748, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=4-Methyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 4-methylbenzeneboronicacid. Compound 748 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 11.65 (bs, 1H), 8.00 (s, 1H), 7.83 (d, J=8.4, 1H), 7.49 (m,3H), 7.29 (d, J=8.0, 2H), 7.13 (s, 1H), 2.42 (s, 3H).

EXAMPLE 427 4-Trifluoromethyl-6-(4-fluorophenyl)-2(1H)-quinolinone(Compound 749, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=4-Fluoro)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 4-fluorobenzeneboronicacid. Compound 749 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.3 (bs, 1H), 7.94 (d, J=8.2, 1H), 7.79 (s, 1H), 7.69 (dd,J=8.4, 5.8, 2H), 7.54 (d, J=8.6, 1H), 7.33 (t, J=8.7, 2H), 7.04 (s, 1H).

EXAMPLE 428 4-Trifluoromethyl-6-(4-methoxyphenyl)-2(1H)-quinolinone(Compound 750, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=4-Methoxy)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available 4-methoxybenzeneboronicacid. Compound 750 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.39 (s, 1H), 7.93 (d, J=8.5, 1H), 7.77 (s, 1H), 7.58 (d,J=8.7, 2H), 7.52 (d, J=8.7, 1H), 7.07 (d, J=8.7, 2H), 7.03 (s, 1H), 3.81(s, 3H).

EXAMPLE 4294-Trifluoromethyl-6-(3,5-bis-trifluoromethyl)phenyl-2(1H)-quinolinone(Compound 751, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=3,5-di-Trifluoromethyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available3,5-di-trifluorobenzeneboronic acid. Compound 751 was isolated as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) 12.02 (bs, 1H), 8.00 (s, 3H),7.92 (s, 1H), 7.84 (dd, J=7.8, 1.9, 1H), 7.58 (d, J=8.5, 1H), 7.19 (s,1H).

EXAMPLE 4304-Trifluoromethyl-6-(4-trifluoromethoxyphenyl)-2(1H)-quinolinone(Compound 752, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=4-Trifluoromethoxy)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available4-trifluoromethoxybenzeneboronic acid. Compound 752 was isolated as awhite solid: ¹H NMR (400 MHz, DMSO-d₆) 8.00 (d, J=8.5, 1H), 7.83 (s,1H), 7.78 (d, J=8.6, 2H), 7.56 (d, J=8.7, 1H), 7.50 (d, J=8.5, 2H), 7.06(s, 1H).

EXAMPLE 431 4-Trifluoromethyl-6-(2,4-dichlorophenyl)-2(1H)-quinolinone(Compound 753, Structure 145 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R²=2,4-Dichloro)

This compound was made according to General Procedure XXIV in Example406 from Compound 308 (Structure 16c of Scheme XXX, where R=H,R¹=trilfuoromethyl) and commercially available2,4-dichlorobenzeneboronic acid. Compound 753 was isolated as a 40 whitesolid: ¹H NMR (400 MHz, DMSO-d₆) 12.47 (s, 1H), 7.77 (d, J=1.8, 1H),7.75 (dd, J=8.4, 1.3, 1H), 7.69 (s, 1H), 7.53 (m, 3H), 7.06 (s, 1H).

EXAMPLE 4323-Fluoro-4-trifluoromethyl-6-(2-fluorophenyl)-2(1H)-quinolinone(Compound 754, Structure 145 of Scheme XXX, Where R=Fluoro,R¹=Trifluoromethyl, R²=2-Fluoro)

This compound was made according to General Procedure XXIV in Example406 from 6-Bromo-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound634, Structure 16c of Scheme XXX, where R=fluoro, R¹=trilfuoromethyl)and commercially available 2-fluorobenzeneboronic acid. Compound 754 wasisolated as a white solid: ¹H NMR (400 MHz, DMSO-d₆) 12.59 (bs, 1H),7.86 (s, 1H), 7.72 (d, J=8.5, 1H), 7.52 (m, 2H), 7.44 (m, 1H), 7.33 (m,2H).

EXAMPLE 4333-Fluoro-4-trifluoromethyl-6-(2,4-dichlorophenyl)-2(1H)-quinolinone(Compound 755, Structure 145 of Scheme XXX, where R=fluoro,R¹=Trifluoromethyl, R²=2,4-Dichloro)

This compound was made according to General Procedure XXIV in Example406 from Compound 634 (Structure 16c of Scheme XXX, where R=fluoro,R¹=trifuoromethyl) and commercially available 2,4-dichlorobenzeneboronicacid. Compound 755 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 12.88 (bs, 1H), 7.80 (s, 1H), 7.72 (m, 2H), 7.58 (m, 2H), 7.49(d, J=8.2, 1H).

EXAMPLE 434 4-Trifluoromethyl-6-(4-hydroxyphenyl)-2(1H)-quinolinone(Compound 756, Structure 146 of Scheme XXX, Where R=H,R¹=Trifluoromethyl, R³=4-Hydroxy)

This compound was prepared in a similar fashion as that described inExample 211 from Compound 750 (Structure 145 of Scheme XXX, where R=H,R¹=trifluoromethyl, R²=4-methoxy). Compound 585 was isolated as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) 12.38 (bs, 1H), 9.67 (bs, 1H), 7.89 (d,J=8.5, 1H), 7.74 (s, 1H), 7.48 (m, 3H), 7.02 (s, 1H), 6.89 (d, J=8.4,1H).

EXAMPLE 435 6-Bromo-4-methyl-2(1H)-quinolinone (Compound 757, Structure16c of Scheme XXX, Where R=H, R¹=Methyl)

This compound was prepared in a similar fashion as that described inExample 1, General Procedure I by Knorr reaction of 4-bromoaniline andethyl acetoacetate. Compound 757 was isolated as a white solid: ¹H NMR(400 MHz, DMSO-d₆) 11.7 (s, 1H), 7.86 (d, J=2.1, 1H), 7.66 (dd, J=7.5,2.1, 1H), 7.27 (d, J=7.5, 1H), 6.45 (s, 1H), 2.41 (s, 3H).

EXAMPLE 436 4-Methyl-6-(3-methoxyphenyl)-2(1H)-quinolinone (Compound758, Structure 145 of Scheme XXX, Where R=H, R¹=Methyl, R²=3-Methoxy)

This compound was made according to General Procedure XXIV in Example406 from Compound 757 (Structure 16c of Scheme XXX, where R=H,R¹=methyl) and commercially available 3-methoxybenzeneboronic acid.Compound 758 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 11.0(s, 1H), 7.88 (d, J=2.0, 1H), 7.74 (dd, J=8.5, 2.1, 1H), 7.51 (d, J=8.5,1H), 7.39 (t, J=7.9, 1H), 7.20 (dt, J=7.9, 1.8, 1H), 7.14 (t, J=1.8,1H), 6.92 (dt, J=7.9, 1.8, 1H), 6.64 (s, 1H), 2.56 (s, 3H).

EXAMPLE 437 4-Methyl-6-(3-chlorophenyl)-2(1H)-quinolinone (Compound 759,Structure 145 of Scheme XXX, Where R=H, R¹=Methyl, R²=3-Chloro)

This compound was made according to General Procedure XXIV in Example406 from Compound 757 (Structure 16c of Scheme XXX, where R=H,R¹=methyl) and commercially available 3-chlorobenzeneboronic acid.Compound 759 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₃) 11.1(s, 1H), 7.83 (d, J=2.0, 1H), 7.72 (dd, J=8.5, 2.1, 1H), 7.60 (t, J=7.9,1H), 7.55-7.35 (m, 4H), 6.65 (s, 1H), 2.58 (s, 3H).

EXAMPLE 438 4-Methyl-6-(3-chloro-2-methylphenyl)-2(1H)-quinolinone(Compound 760, Structure 145 of Scheme XXX, Where R=H, R¹=Methyl,R²=3-Chloro-2-methyl).

This compound was made according to General Procedure XXIV in Example406 from Compound 757 (Structure 16c of Scheme XXX, where R=H,R¹=methyl) and-commercially available 3-chloro-2-methylbenzeneboronicacid. Compound 760 was isolated as a white solid: ¹H NMR (400 MHz,DMSO-d₆) 11.70 (s, 1H), 7.65-7.25 (m, 6H), 6.45 (s, 1H), 2.43 (s, 3H),2.27 (s, 3H).

EXAMPLE 439 4-Methyl-6-(2,3-dichlorophenyl)-2(1H)-quinolinone (Compound761, Structure 145 of Scheme XXX, Where R=H, R¹=Methyl, R²=2,3-Dichloro)

This compound was made according to General Procedure XXIV in Example406 from Compound 757 (Structure 16c of Scheme XXX, where R=H,R¹=methyl) and commercially available 2,3-dichlorobenzeneboronic acid.Compound 761 was isolated as a white solid: ¹H NMR (400 MHz, DMSO-d₆)11.70 (s, 1H), 7.75-7.35 (m, 6H), 6.43 (s, 1H), 2.45 (s, 3H).

EXAMPLE 440 4-Methyl-6-(2,4-dichlorophenyl)-2(1H)-quinolinone (Compound762, Structure 145 of Scheme XXX, Where R=H, R¹=Methyl, R²=2,4-Dichloro)

This compound was made according to General Procedure XXIV in Example406 from Compound 757 (Structure 16c of Scheme XXX, where R=H,R¹=methyl) and commercially available 2,4-dichlorobenzeneboronic acid.Compound 762 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₆)11.00 (s, 1H), 7.72 (s, 1H), 7.57 (d, J=8.5, 1H), 7.53 (s, 1H),7.40-7.30 (m, 3H), 6.61 (s, 1H), 2.52 (s, 3H).

EXAMPLE 441 4-Methyl-6-(2-methylphenyl)-2(1H)-quinolinone (Compound 763,Structure 145 of Scheme XXX, Where R=H, R¹=Methyl, R²=2-Methyl)

This compound was made according to General Procedure XXIV in Example406 from Compound 757 (Structure 16c of Scheme XXX, where R=H,R¹=methyl) and commercially available 2-methylbenzeneboronic acid.Compound 763 was isolated as a white solid: ¹H NMR (400 MHz, CDCl₆)11.00 (s, 1H), 7.62 (s, 1H), 7.50 (s, 2H), 7.35-7.27 (m, 4H), 6.65 (s,1H), 2.52 (s, 3H), 2.30 (s, 3H).

EXAMPLE 442 4-Trifluoromethyl-6-phenyl-2(1H)-quinolinone (Compound 764,Structure 145 of Scheme XXX, Where R=H, R¹=Trifluoromethyl, R²=H)

This compound was made according to General Procedure I in Example 1 byKnorr reaction of 4-phenylaniline (Structure 147 of Scheme XXX, whereR²=H) and ethyl 4,4,4-trifluoroacetoaceate. Compound 764 was isolated asa white solid: ¹H NMR (400 MHz, CDCl₃) 11.61 (s, 1H), 8.05 (s, 1H), 7.87(d, J=8.6, 1H), 7.61 (d, J=7.4, 2H), 7.50 (m, 3H), 7.43 (t, J=7.4, 1H),7.16 (s, 1H).

EXAMPLE 443 4-Trifluoromethyl-6-propio-2(1H)-quinolinone (Compound 765,Structure 149 of Scheme XXXI, Where R=Ethyl)

4-Trifluoromethyl-6-propio-2-isopropyloxyquinoline (Compound 766,Structure 148 of, Scheme XXXI, Where R=ethyl):

This compound was prepared according to the, following General ProcedureXXV:

To a solution of Compound 309 (Structure 17 of Scheme XXXI) in THF at−70° C. was added n-BuLi and the mixture was stirred for 10 min. AWeinreb's amide such as N-methyl-N-methoxypropionamide in THF was addedto the reaction mixture and the reaction was slowly warmed up to rt andquenched with water. Extraction with EtOAc and washing the organic layerwith brine afforded a crude mixture, which was concentrated andchromatographied to give Compound 766.

4-Trifluoromethyl-6-propio-2(1H)-quinolinone (Compound 765, Structure149 of Scheme XXXI, Where R=Ethyl):

Compound 765 was prepared from Compound 766 upon hydrolysis that isdescribed in Example 101 as General procedure XIV. ¹H NMR (400 MHz,acetone-d₆) 11.40 (s, 1H), 8.41 (s, 1H), 8.26 (d, J=8.7, 1H), 7.61 (d,J=8.7, 1H), 7.03 (s, 1H), 3.11 (q, J=6.9, 2H), 1.19 (t, J=6.9, 3H).

EXAMPLE 444 4-Trifluoromethyl-6-(1-ethylaminopropyl)-2(1H)-quinolinone(Compound 767, Structure 150 of Scheme XXXI, Where R¹=Ethyl, R²=H)

To a mixture of Compound 765 (Structure 149 of Scheme XXXI) andethylamine in methanol were added TFA and NaCNBH₃. The reaction mixturewas stirred at rt for 1 h, quenched with water, extracted with EtOAc andconcentrated. Chromatography afforded Compound 767 as white solid. ¹HNMR (400 MHz, acetone-d₆) 11.60 (s, 1H), 7.75 (s, 1H), 7.67 (dd, J=8.5,1.6, 1H) 7.50 (d, J=8.5, 1H), 6.90 (s, 1H), 3.69 (t, J=6.5, 1H), 3.31(s, 1H), 2.64-2.48 (m, 1H), 2.46-2.38 (m, 1H), 1.81-1.70 (m, 1H),1.68-1.60 (m, 1H), 1.04 (t, J=7.1, 3H), 0.82 (t, J=7.4, 3H).

EXAMPLE 4454-Trifluoromethyl-6-(1-N-ethyl-N-methylaminopropyl)-2(1H)-quinolinone(Compound 768, Structure 150 of Scheme XXXI, Where R¹=Ethyl, R²=Methyl)

This compound was prepared from Compound N 16 and formaldehyde in asimilar fashion as that described in Example 2, General procedure IV asa white solid. ¹H NMR (400 MHz, acetone-d₆) 11.42 (s, 1H), 7.64 (s, 1H),7.61 (d, J=8.5, 1H) 7.51 (d, J=8.5, 1H), 2.54-2.48 (m, 1H), 2.36-2.32(m, 1H), 2.20 (s, 3H), 2.01-1.95 (m, 1H), 1.79-1.72 (m, 1H), 1.01 (t,J=7.0, 3H), 0.77 (t, J=7.3, 3H).

EXAMPLE 4464-Trifluoromethyl-6-(1-hydroxy-1-methyl-2-oxopropyl)-2(1H)-quinolinone(Compound 769, Structure 152 of Scheme XXXI, Where R¹=Methyl, R¹=Acetyl)

4-Trifluoromethyl-6-(1-hydroxy-1-methyl-2,2-dimethoxypropyl)-2-isopropyloxyquinoline(Compound 770, Structure 151 of Scheme XXXI, R=Methyl,R¹=1,1-Dimethoxyethyl):

This compound was prepared from Compound 309 (Structure 17 of SchemeXXXI) and 3,3-dimethoxy-2-butanone in a similar fashion as thatdescribed in Example 330, General procedure XIX.

4-Trifluoromethyl-6-(1-hydroxy-1-methyl-2-oxopropyl)-2(1H)-quinolinone(Compound 769, Structure 152 of Scheme XXXI, Where R¹=Methyl,R¹=Acetyl):

This compound was prepared from hydrolysis of Compound 770 in a similarfashion as that described in Example 101, General Procedure XIV asyellow oil. ¹H NMR (400 MHz, CDCl₃) 10.72 (s, 1H), 7.96 (s, 1H), 7.68(d, J=8.9, 1H), 7.50 (d, J=8.9, 1H), 7.13 (s, 1H), 4.62 (s, 1H), 2.12(d, J=1.9, 3H), 1.8 (s, 1H).

EXAMPLE 4474-Trifluoromethyl-6-(4,4,4-trifluoro-1(E)-butenyl)-2(1H)-quinolinone(Compound 771, Structure 153 of Scheme XXXI, Where R²=H,R³=2,2,2-Trilfuoroethyl)

4-Trifluoromethyl-6-(4,4,4-trifluorobutyro)-2-isopropyloxyquinoline(Compound 772, Structure 148 of Scheme XXXI, WhereR=3,3,3-Trifluoropropyl):

This compound was prepared in a similar fashion as that described inExample 443, General Procedure XXV from Compound 309 (Structure 17 ofScheme XXXI) and N-methyl-N-methoxybutyramide.

4-Trifluoromethyl-6-(1-hydroxy-4,4,4-trifluorobutyl)-2-isopropyloxyquinoline(Compound 773, Structure 152 of Scheme XXXI, Where R=H,R¹=3,3,3-Trifluoropropyl):

This compound was prepared in a similar fashion as that described inExample 358, General Procedure XXI from Compound 772.

4-Trifluoromethyl-6-(4,4,4-trifluoro-1(E)-butenyl)-2(1H)-quinolinone(Compound 771, Structure 153 of Scheme XXXI, Where R²=H,R³=2,2,2-Trilfuoroethyl):

This compound was prepared in a similar fashion as that described inExample 101, General Procedure XIV from Compound 773 as the onlyproduct. ¹H NMR (400 MHz, acetone-d₆) 11.17 (s, 1H), 7.89 (d, J=8.1,1H), 7.75 (s, 1H), 7.53 (d, J=8.6, 1H), 6.96 (s, 1H), 6.89 (d, J=15.9,1H), 6.33-6.25 (m, 1H), 3.26-3.17 (m, 1H).

EXAMPLE 4484-Trifluoromethyl-6-(1-(3,3,3-trifluoropropyl)-1(E)-propenyl)-2(1H)-quinolinone(Compound 774, Structure 153 of Scheme XXXI, WhereR²=3,3,3-Trifluoropropyl, R³=Methyl)

4-Trifluoromethyl-6-(1-ethyl-1-hydroxy-4,4,4-trifluorobutyl)-2-isopropyloxyquinoline(Compound 775, Structure 151 of Scheme XXXI, Where R=Methyl,R¹=3,3,3-Trifluoropropyl):

To a solution of Compound 772 (Structure 148 of Scheme XXXI, whereR=3,3,3-trifluoropropyl) in THF was added EtMgBr in THF and the reactionmixture was stirred at rt overnight till the starting material wasconsumed by TLC. The reaction was quenched by water, extracted withEtOAc, washed with brine and concentrated. Chromatography affordedCompound 775 as oil.

4-Trifluoromethyl-6-(1-(3,3,3-trifluoropropyl)-1(E)-propenyl)-2(1H)-quinolinone(Compound 774, Structure 153 of Scheme XXXI, WhereR²=3,3,3-Trifluoropropyl, R³=methyl):

This compound was prepared in a similar fashion as that described inExample 101, General Procedure XIV from Compound 775 as yellow oil. ¹HNMR (500 MHz, CDCl₃) 11.99 (s, 1H), 7.60 (s, 1H), 7.47 (d, J=8.5, 1H),7.43 (dd, J=8.5, 2.0, 1H), 7.13 (s, 1H), 5.76 (q, J=7.0, 1H), 2.66 (t,J=8.5, 2H), 2.12-2.05 (m, 2H), 1.66 (d, J=7.0, 3H).

EXAMPLE 4494-Trifluoromethyl-6-(1-ethyl-4,4,4-trifluoro-1(E)-butenyl)-2(1H)-quinolinone(Compound 776, Structure 153 of Scheme XXXI R²=Ethyl,R³=2,2,2-Trifluoroethyl) and4-Trifluoromethyl-6-(1-ethyl-4,4,4-trifluoro-1(Z)-butenyl)-2(1H)-quinolinone(Compound 777, Structure 153 of Scheme XXXI, R²=Ethyl,R³=2,2,2-Trifluoroethyl)

Compound 776 was isolated from the hydrolysis of Compound 775, Structure151 of Scheme XXXI, where R=ethyl, R¹=3,3,3-trifluoropropyl) as thatdescribed in Example 448 as the E-isomer. ¹H NMR (500 MHz, CDCl₃) 11.02(s, 1H), 7.77 (s, 1H), 7.61 (dd, J=8.5, 2.0, 1H), 7.39 (s, 1H), 7.34 (d,J=8.5, 1H), 7.10 (s, 1H), 5.63 (t, J=7.5, 1H), 3.08-3.02 (m, 2H), 2.57(q, J=7.5, 2H), 1.01 (t, J=7.5, 3H).

Compound 777 was isolated from the hydrolysis of Compound 775, Structure151 of Scheme XXXI, where R=ethyl, R¹=3,3,3-trifluoropropyl) as thatdescribed in Example 448 as the Z-isomer. ¹H NMR (500 MHz, CDCl₃) 11.60(s, 1H), 7.56 (s, 1H), 7.37 (s, 2H), 7.09 (s, 1H), 5.52-5.57 (m, 1H),2.71-2.66 (m, 2H), 2.45-2.40 (m, 2H), 1.02 (t, J=7.4, 3H).

EXAMPLE 4502-Chloro-4-trifluoromethyl-6-(bis-N,N-2,2,2-trifluoroethyl)aminoquinoline(Compound 778, Structure 154 of Scheme XXXII, WhereR¹=R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 223 (Structure 7 of SchemeXXXII, where R=R²=2,2,2-trifluoroethyl) from the following procedure.

To the quinolinone (20.0 mg, 0.05 mmol) in toluene (0.25 mL) was addedPOCl₃ (30.0 microlitres, 0.30 mmole, 6 equiv). The resulting reactionmixture was heated to 110° C. for 4-8 h, cooled to rt, diluted with EA(25 mL) and washed with 20% KOH (2×25 mL). The organic layers were driedover MgSO₄, filtered, and concentrated in vacuo. Purification of theresulting oil by flash chromatography (EtOAc:hexane mixtures) affordedthe 2-chloro-6-amino-quinolines.

Compound 778 was isolated as yellow solid; ¹H NMR (CDCl₃, 500 MHz) 8.06(d, J=9.8, 1H), 7.66 (s, 1H), 7.53 (dd, J=2.4, 9.3, 1H), 7.41 (bs, 1H),4.21 (q, J=8.3, 4H).

EXAMPLE 4512-Methoxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 779, Structure 155 of Scheme XXXII, Where R=Methoxy,R¹=R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 778 from the following GeneralProcedure XXVI:

A mixture of Compound 778 (Structure 154 of Scheme XXXII, whereR¹=R²=2,2,2-trifluoroethyl) NaOMe (1.5 equiv) in methanol was heated atreflux for 2 h till the starting material was consumed by TLC. Thereaction was quenched by water and a solid was precipitated. Filtrationfollowed washing with methanol afforded the 2-methoxyquinoline in 70-90%yield.

Compound 779 was isolated as a white solid. ¹H NMR (400 MHz, acetone-d₆)7.89 (d, J=9.3, 1H) 7.77 (dd, J=9.1, 2.3, 1H), 7.49 (s, 1H), 7.30 (s,1H), 4.51 (q, J=8.6, 4H), 4.05 (s, 3H).

EXAMPLE 4522-Isopropyloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 780, Structure 155 of Scheme XXXII, Where R=Isopropyloxy,R¹=R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 223 in a similar fashion asthat described in Example 101, General Procedure XII as yellow oil. ¹HNMR (400 MHz, acetone-d₆) 7.71 (d, J=9.3, 1H) 7.61 (dd, J=9.3, 2.8, 1H),7.35 (s, 1H), 7.08 (s, 1H), 5.40-5.34 (m, 1H), 4.36 (q, J=8.7, 4H), 1.25(d, J=6.2, 6H).

EXAMPLE 4532-Ethoxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 781, Structure 155 of Scheme XXXII, Where R=Ethoxy,R¹=R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 778 (Structure 154 of SchemeXXXII, where R¹=R²=2,2,2-trifluoroethyl) in a similar fashion as thatdescribed in Example 451, General Procedure XXVI as yellow oil. ¹H NMR(500 MHz, CDCl₃) 7.83 (d, J=10.2, 1H), 7.39-7.37 (m, 2H), 7.21 (s, 1H),4.51 (q, J=6.8, 2H), 4.14 (q, J_(H-F)=8.8, 4H), 1.44 (t, J=6.8, 3H).

EXAMPLE 4542-Acetyloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline,(Compound 782, Structure 155 of Scheme XXXII, Where R=Acetyloxy,R¹=R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 223 and acetic anhydride by thefollowing General Procedure XXVII.

To a solution of 220 mg (0.46 mmol) of Compound 223 (Structure 7 ofScheme XXXII, where R¹=R²=2,2,2-trifluoroethyl) in 10 mL THF in a 100 mLrb flask was added Et₃N (0.3 mL, 2.5 mmol) followed by Ac₂O (0.3 mL, 4mmol) and DMAP (5 mg, 0.01 eq). The mixture was stirred at rt for 3 hand then 50 mL water was added. Extracted with 50 mL EtOAc, and theorganic layer was quickly washed with 2.5 N HCl (2×50 mL), sat NaHCO₃,and brine, and dried over MgSO₄. Concentration and purification bychromatography (silica gel, hex: EtOAc 5:1) afforded 192 mg of Compound782 as yellow solid. ¹H NMR (500 MHz, CDCl₃) 8.02 (d, J=9.8, 1H), 7.51(dd, J=9.3, 2.9, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 4.20 (q, J_(H-F)=8.8,4H), 2.41 (s, 3H).

EXAMPLE 4552-(2-Dimethylamino)ethoxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 783, Structure 155 of Scheme XXXII, WhereR=2-Dimethylaminoethoxy, R¹=R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 778 (Structure 154 of SchemeXXXII, where R¹=R²=2,2,2-trifluoroethyl) and 2-dimethylaminoethanol in asimilar fashion as that described in Example 451, General Procedure XXVIas yellow oil. ¹H NMR (400 MHz, CDCl₃) 7.83 (d, J=10.4, 1H), 7.30-7.39(m, 2H), 7.28 (s, 1H), 4.57 (t, J=5.5, 2H), 4.14 (q, J=8.4, 2H), 2.76(t, J=5.5, 2H), 2.36 (s, 6H).

EXAMPLE 4562-Isobutyryloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinolineCompound 784, Structure 155 of Scheme XXXII, Where R=Isobutyryloxy.R¹=R² =2,2,2-Trifluoroethyl)

This compound was prepared from Compound 223 (Structure 7 of SchemeXXXII, where R¹=R²=2,2,2-trifluoroethyl) and isobutyric anhydride in asimilar fashion as that described in Example 454, General ProcedureXXVII as a yellow solid. ¹H NMR (500 MHz, CDCl₃) 8.04 (d, J=9.3, 1H),7.50 (dd, J=9.3, 2.9, 1H), 7.45 (s, 1H), 7.44 (s, 1H), 4.20 (q,J_(H-F)=8.8, 4H), 2.95-2.89 (m, 1H), 1.39 (d, J=6.8, 6H).

EXAMPLE 4572-(2,2-Dimethyl)propyryloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)-aminoquinoline(Compound 785, Structure 155 of Scheme XXXII, Where R=tert-Butyryloxy,R¹=R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 223 (Structure 7 of SchemeXXXII, where R¹=R²=2,2,2-trifluoroethyl) and valeric anhydride in asimilar fashion as that described in Example 454, General ProcedureXXVII as a yellow solid. ¹H NMR (500 MHz, CDCl₃) 8.05 (d, J=9.3, 1H),7.50 (dd, J=9.3, 2.9, 1H), 7.45 (s, 1H), 7.42 (s, 1H), 4.20 (q,J_(H-F)=8.3, 4H), 1.45 (s, 9H).

EXAMPLE 4582-N,N-Dimethylcarbamyloxy-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)-aminoquinoline(Compound 786, Structure 155 of Scheme XXXII, WhereR=Dimethylaminocarbonyloxy, R¹=R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 223 (Structure 7 of SchemeXXXII, where R¹=R²=2,2,2-trifluoroethyl) and dimethylcarbamyl chloridein a similar fashion as that described in Example 454, General ProcedureXXVII as a yellow solid. ¹H NMR (500 MHz, CDCl₃) 8.02 (d, J=9.3, 1H),7.55 (s, 1H), 7.49 (dd, J=9.3, 2.9, 1H), 7.44 (s, 1H), 4.19 (q,J_(H-F)=8.3, 4H), 3.18 (s, 1H), 3.06 (s, 3H).

EXAMPLE 4592-Cyano-4-trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)aminoquinoline(Compound 787, Structure 155 of Scheme XXXII, Where R=Cyano,R¹=R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 778 (Structure 154 of SchemeXXXII, where R¹=R²=2,2,2-trifluoroethyl) in a similar fashion as thatdescribed in Example 451, General Procedure XXVI as yellow solid. ¹H NMR(CDCl₃, 500 MHz) 8.21 (d, J=9.8, 1H), 7.92 (s, 1H), 7.63 (dd, J=2.9,9.8, 1H), 7.42 (s, 1H), 4.27 (q, J=8.4, 4H).

EXAMPLE 4604-Trifluoromethyl-6-(bis-2,2,2-trifluoroethyl)amino-2(1H)-quinolinoneoxime (Compound 788, Structure 156 of Scheme XXXII, Where R=H,R,¹=R²=2,2,2-Trifluoroethyl)

This compound was prepared from Compound 223 (Structure 7 of SchemeXXXII, where R¹=R²=2,2,2-trifluoroethyl) as yellow solid. ¹H NMR (CDCl₃,500 MHz) 11.20-11.40 (bs, 1H), 7.72 (s, 1H), 7.36 (d, J=10.2, 1H),7.28-7.31 (m, 2H), 4.11 (q, J=8.3, 4H).

EXAMPLE 4616-(N-2,2,2-Trifluoroethyl-N-nitroso)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 789, Structure 157 of Scheme XXXIII, WhereR=2,2,2-Trifluoroethyl)

A 100 mL rb flask was charged with a solution of Compound 209 (Structure7a of Scheme XXXIII, where R=2,2,2-trifluoroethyl) (410 mg, 1.32 mmol)in 15 mL conc. HCl and cooled in an ice bath. A solution of NaNO₂ (170mg, 2.5 mmol, 2 eq) in 5 mL water was added dropwise in 20 min and themixture was stirred in an ice bath for 2 h, then 10 mL water was addedand the solids were filtered and washed with water to give Compound 789as white solid. ¹H NMR (500 MHz, acetone-d₆) 11.4 (bs, 1H), 8.01-7.98(m, 2H), 7.75 (d, J=9.3, 1H), 7.08 (s, 1H), 5.06 (q, J_(H-F)=9.3, 2H).

EXAMPLE 4626-(N-Isobutyl-N-nitroso)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 790 Structure 157 of Scheme XXXIII, Where R=Isobutyl)

This compound was prepared in a similar fashion as that described inExample 461 from Compound 206 (Structure 7a of Scheme XXXIII, whereR=isobutyl) and isolated as white solid. ¹H NMR (500 MHz, CDCl₃) 12.0(bs, 1H), 7.94 (dd, J=9.3, 2.0, 1H), 7.88 (s, 1H), 7.56 (d, J=9.3, 1H),7.18 (s, 1H), 3.95 (d, J=7.3, 2H), 2.05-2.00 (m, 1H), 0.88 (d, J=6.8,6H).

EXAMPLE 4636-(N-Isobutyl-N-nitroso)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 791, Structure 158 of Scheme XXXIII, WhereR=2,2,2-Trifluoroethyl, R¹=H, R²=Isopropyl)

Compound 789 (Structure 157 of Scheme XXXIII, whereR=2,2,2-trifluoroethyl) was dissolved in a mixture of EtOH (15 mL) andHOAc (10 mL) in a 100 mL rb flask, cooled in an ice bath, and zinc dust(0.5 g, 7.7 mmol, 6 eq) was added in small portions in 20 min. Thebright yellow suspension was stirred at rt for 16 h, filtered and rinsedwith EtOAc (50 mL) and water (50 mL). 20 mL brine was added and thelayers were separated. The water layer was extracted with 50 mL EtOAc,and the combined organic layers were washed with brine (50 mL), anddried over MgSO₄. Concentration and purification by chromatography(Silica gel, hex: EtOAc 3:1 to 1:1 gradient) afforded an inseparablemixture of starting material and hydrazine, that was used in the nextstep.

To a solution of the above mixture (12 mg, 0.04 mmol) in 5 mL TFA in a100 mL rb flask was added acetone (0.2 mL, excess) and the mixture wasstirred at rt for 6 h. NaCNBH₃ (200 mg, 3.3 mmol) was added in portionsover a 2 hour period, and the mixture was stirred at rt for 16 h. 20 mLwater was slowly added and the water layer was extracted with EtOAc(3×25 mL). The combined org. layers were washed with brine and driedover MgSO₄. Concentration in vacuo and purification by columnchromatography (Silica gel, hex:EtOAc 4:1 to 2:1 gradient) affordedCompound 791 as yellow solid. ¹H NMR (500 MHz, DMSO-d₆) 11.5 (bs, 1H),7.39-7.37 (m, 2H), 7.31 (d, J=9.8, 1H), 7.08 (s, 1H), 4.09 (q, J=8.8,2H), 3.77 (s, 1H), 3.25-3.20 (m, 1H), 1.06 (d, J=6.3, 6H).

EXAMPLE 4646-(4,5-Dihydro-3-methyl-1-pyrazoly)-4-trifluoromethylquinolin-2(1H)-one(Compound 792, Structure 160 of Scheme XXXIII, Where R¹=Methyl, R²=H)

6-Hydrazino-4-trifluoromethylquinolin-2(1H)-one (Compound 793, Structure159 of Scheme XXXIII)

In a 250 mL rb flask a suspension of Compound 200 (structure 3 of SchemeXXXIII) (2.28 g, 10 mmol) in 10 mL conc. HCl was cooled to −1° C. and asolution of NaNO₂ (0.40 g, 12 mmol) in water (5 mL) was added dropwisein 20 min. The dark yellow suspension was stirred at −1° C. for 1 h andthen a solution of SnCl₂.2H₂O (5.2 g, 15 mmol) in conc HCl (10 mL) wasadded dropwise in 10 min. The light yellow suspension of Compound 793was stirred at −1° C. for 2 h and then used directly or kept in arefrigerator at −1° C. until it was used (the crude compound can bestored for at least one month without decomposition).

6-(4,5-Dihydro-3-methyl-1-pyrazoly)-4-trifluoromethylquinolin-2(1H)-one(Compound 792, Structure 160 of Scheme XXXIII, Where R¹=Methyl, R²=H)

This compound was prepared by condensation of Compound 793 and1-buten-3-one as yellow solid. ¹H NMR (500 MHz, CDCl₃) 10.2 (bs, 1H),7.55 (dd, J=8.8, 2.4, 1H), 7.21 (d, J=8.8, 1H), 7.11 (bs, 1H), 7.05 (s,1H), 3.72 (t, J=10.0, 2H), 2.90 (t, J=10.2, 2H), 2.11 (s, 3H).

EXAMPLE 465(±)-6-(4,5-Dihydro-3-ethyl-5-methyl-1-pyrazoly)-4-trifluoromethylquinolin-2(1H)-one(Compound 794, Structure 160 of Scheme XXXIII, Where R¹=ethyl,R²=Methyl)

This compound was prepared from the condensation of Compound 793(Structure 159 of Scheme XXXIII) and 2-hexen-4-one as yellow solid. ¹HNMR (500 MHz, DMSO-d₆) 12.1 (bs, 1H), 7.41 (dd, J=8.8, 2.4, 1H), 7.34(d, J=8.8, 1H), 7.21 (bs, 1H), 6.92 (s, 1H), 4.37-4.28 (m, 1H), 3.12(dd, J=17.1, 10.2, 1H), 2.53 (dd, J=17.1, 4.9, 1H), 2.37 (q, J=7.3, 2H),1.12 (t, J=7.3, 3H), 1.12 (d, J=5.9, 3H).

EXAMPLE 4666-(N-Acetyl-N-dimethylimino)amino-4-trifluoromethylquinolin-2(1H)-one(Compound 795, Structure 161 of Scheme XXXIII)

A mixture of Compound 793 (Structure 159 of Scheme XXXIII) and aceticacid in acetone was heated in a sealed tube at 100° C. for 2 h. Thereaction mixture was concentrated and chromatographied to affordCompound 795 as major product as yellow solid. ¹H NMR (500 MHz, DMSO-d₆)12.5 (bs, 1H), 7.79 (dd, J=9.3, 2.4, 1H), 7.65 (s, 1H), 7.54 (d, J=9.3,1H), 7.08 (s, 1H), 2.22 (s, 3H), 2.14 (s, 3H), 1.94 (s, 3H).

Steroid Receptor Activity

Utilizing the “cis-trans” or “co-transfection” assay described by Evanset al., Science, 240:889-95 (May 13, 1988), the disclosure of which isherein incorporated by reference, the compounds of the present inventionwere tested and found to have strong, specific activity as bothagonists, partial agonists and antagonists of AR. This assay isdescribed in further detail in U.S. Pat. Nos. 4,981,784 and 5,071,773,the disclosures of which are incorporated herein by reference.

The co-transfection assay provides a method for identifying functionalagonists and partial agonists which mimic, or antagonists which inhibit,the effect of native hormones, and quantifying their activity forresponsive IR proteins. In this regard, the co-transfection assay mimicsan in vivo system in the laboratory. Importantly, activity in theco-transfection assay correlates very well with known in vivo activity,such that the co-transfection assay functions as a qualitative andquantitative predictor of a tested compounds in vivo pharmacology. See,e.g., T. Berger et al. 41 J. Steroid Biochem. Molec. Biol. 773 (1992),the disclosure of which is herein incorporated by reference.

In the co-transfection assay, a cloned cDNA for an IR (e.g., human PR,AR or GR) under the control of a constitutive promoter (e.g., the SV 40promoter) is introduced by transfection (a procedure to induce cells totake up foreign genes) into a background cell substantially devoid ofendogenous IRs. This introduced gene directs the recipient cells to makethe IR protein of interest. A second gene is also introduced(co-transfected) into the same cells in conjunction with the IR gene.This second gene, comprising the cDNA for a reporter protein, such asfirefly luciferase (LUC), controlled by an appropriate hormoneresponsive promoter containing a hormone response element (HRE). Thisreporter plasmid functions as a reporter for thetranscription-modulating activity of the target IR. Thus, the reporteracts as a surrogate for the products (mRNA then protein) normallyexpressed by a gene under control of the target receptor and its nativehormone.

The co-transfection assay can detect small molecule agonists orantagonists of target IRs. Exposing the transfected cells to an agonistligand compound increases reporter activity in the transfected cells.This activity can be conveniently measured, e.g., by increasingluciferase production, which reflects compound-dependent, IR-mediatedincreases in reporter transcription. To detect antagonists, theco-transfection assay is carried out in the presence of a constantconcentration of an agonist to the target IR (e.g., progesterone for PR)known to induce a defined reporter signal. Increasing concentrations ofa suspected antagonist will decrease the reporter signal (e.g.,luciferase production). The co-transfection assay is therefore useful todetect both agonists and antagonists of specific IRs. Furthermore, itdetermines not only whether a compound interacts with a particular IR,but whether this interaction mimics (agonizes) or blocks (antagonizes)the effects of the native regulatory molecules on target geneexpression, as well as the specificity and strength of this interaction.

The activity of selected steroid receptor modulator compounds of thepresent invention were evaluated utilizing the co-transfection assay,and in standard IR binding assays, according to the followingillustrative Examples.

EXAMPLE 467 Co-transfection Assay

CV-1 cells (African green monkey kidney fibroblasts) were cultured inthe presence of Dulbecco's Modified Eagle Medium (DMEM) supplementedwith 10% charcoal resin-stripped fetal bovine serum then transferred to96-well microtiter plates one day prior to transfection.

To determine AR agonist and antagonist activity of the compounds of thepresent invention, the CV-1 cells were transiently transfected bycalcium phosphate coprecipitation according to the procedure of Bergeret al., 41 J. Steroid Biochem. Mol. Biol., 733 (1992) with the followingplasmids: pShAR (5 ng/well), MTV-LUC reporter (100 ng/well), pRS-β-Gal(50 ng/well) and filler DNA (pGEM; 45 ng/well). The receptor plasmid,pRShAR, contains the human AR under constitutive control of the SV-40promoter, as more fully described in J. A. Simental et al.,“Transcriptional activation and nuclear targeting signals of the humanandrogen receptor”, 266 J. Biol. Chem., 510 (1991).

The reporter plasmid, MTV-LUC, contains the cDNA for firefly luciferase(LUC) under control of the mouse mammary tumor virus (MTV) long terminalrepeat, a conditional promoter containing an androgen response element.See e.g, Berger et al. supra. In addition, pRS-β-Gal, coding forconstitutive expression of E. coli β-galactosidase (β-Gal), was includedas an internal control for evaluation of transfection efficiency andcompound toxicity.

Six hours after transfection, media was removed and the cells werewashed with phosphate-buffered saline (PBS). Media containing referencecompounds (i.e. progesterone as a PR agonist, mifepristone ((11 beta,17beta)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one:RU486; Roussel Uclaf) as a PR antagonist; dihydrotestosterone (DHT;Sigma Chemical) as an AR agonist and 2-OH-flutamide (the activemetabolite of 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]pronanamide;Schering-Plough) as an AR antagonist; estradiol (Sigma) as an ER agonistand ICI 164,384 (N-butyl-3,17-dihydroxy-N-methyl-(7-alpha,17-beta)-estra-1,3,5(10)-triene-7-undecanamide; ICI Americas) as an ERantagonist; dexamethasone (Sigma) as a GR agonist and RU486 as a GRantagonist; and aldosterone (Sigma) as a MR agonist and spironolactone((7-alpha-[acetylthio]-17-alpha-hydroxy-3-oxopregn-4-ene-21-carboxylicacid gamma-lactone; Sigma) as an MR antagonist) and/or the modulatorcompounds of the present invention in concentrations ranging from 10⁻¹²to 10⁻⁵ M were added to the cells. Three to four replicates were usedfor each sample. Transfections and subsequent procedures were performedon a Biomek 1000 automated laboratory work station.

After 40 hours, the cells were washed with PBS, lysed with a TritonX-100-based buffer and assayed for LUC and β-Gal activities using aluminometer or spectrophotometer, respectively. For each replicate, thenormalized response (NR) was calculated as:

LUC response/β-Gal rate

where β-Gal rate=β-Gal·1×10⁻⁵/β-Gal incubation time.

The mean and standard error of the mean (SEM) of the NR were calculated.Data was plotted as the response of the compound compared to thereference compounds over the range of the dose-response curve. Foragonist experiments, the effective concentration that produced 50% ofthe maximum response (EC₅₀) was quantified. Agonist efficacy was afunction (%) of LUC expression relative to the maximum LUC production bythe reference agonist for PR, AR, ER, GR or MR. Antagonist activity wasdetermined by testing the amount of LUC expression in the presence of afixed amount of DHT as an AR agonist and progesterone as a PR agonist atthe EC₅₀ concentration. The concentration of test compound thatinhibited 50% of LUC expression induced by the reference agonist werequantified (IC₅₀). In addition, the efficacy of antagonists wasdetermined as a function (%) of maximal inhibition.

IR Binding Assay

AR Binding: For the whole cell binding assay, COS-1 cells in 96-wellmicrotiter plates containing DMEM-10% FBS were transfected as describedabove with the following plasmid DNA: pRShAR (2 ng/well), pRS-β-Gal (50ng/well) and pGEM (48 ng/well). Six hours after transfection, media wasremoved, the cells were washed with PBS and fresh media was added. Thenext day, the media was changed to DMEM-serum free to remove anyendogenous ligand that might be complexed with the receptor in thecells.

After 24 hours in serum-free media, either a saturation analysis todetermine the K_(d) for tritiated dihydrotestosterone (³H-DHT) on humanAR or a competitive binding assay to evaluate the ability of testcompounds to compete with ³H-DHT for AR was performed. For thesaturation analysis, media (DMEM-0.2% CA-FBS) containing ³H-DHT (inconcentrations ranging from 12 nM to 0.24 nM) in the absence (totalbinding) or presence (non-specific binding) of a 100-fold molar excessof unlabeled DHT were added to the cells. For the competitive bindingassay, media containing 1 nM ³H-DHT and test compounds in concentrationsranging from 10⁻¹⁰ to 10⁻⁶ M were added to the cells. Three replicateswere used for each sample. After three hours at 37° C., an aliquot ofthe total binding media at each concentration of ³H-DHT was removed toestimate the amount of free ³H-DHT. The remaining media was removed, thecells were washed three times with PBS to remove unbound ligand, andcells were lysed with a Triton X-100-based buffer. The lysates wereassayed for amount of bound ³H-DHT and β-Gal activity using ascintillation counter or spectrophotometer, respectively.

For the saturation analyses, the difference between the total bindingand the nonspecific binding, normalized by the β-Gal rate, was definedas specific binding. The specific binding was evaluated by Scatchardanalysis to determine the K_(d) for ³H-DHT. See e.g., D. Rodbard,“Mathematics and statistics of ligand assays: an illustrated guide” In:J. Langon and J. J. Clapp, eds., Ligand Assay, Masson Publishing U.S.A.,Inc., New York, pp. 45-99, (1981), the disclosure of which is hereinincorporated by reference. For the competition studies, the data wasplotted as the amount of ³H-DHT (% of control in the absence of testcompound) remaining over the range of the dose-response curve for agiven compound. The concentration of test compound that inhibited 50% ofthe amount of ³H-DHT bound in the absence of competing ligand wasquantified (IC₅₀) after log-logit transformation. The K_(i) values weredetermined by application of the Cheng-Prusoff equation to the IC₅₀values, where: $\underset{\_}{{IC}_{50}}$K_(i) = (1 + [³H-DHT])/K_(d)  for  ³H-DHT

After correcting for non-specific binding, IC₅₀ values were determined.The IC₅₀ value is defined as the concentration of competing ligandneeded to reduce specific binding by 50%. The IC₅₀ value was determinedgraphically from a log-logit plot of the data. The K_(i) values weredetermined by application of the Cheng-Prusoff equivuation to the IC₅₀values, the labeled ligand concentration and the K_(d) of the labeledligand.

The agonist, antagonist and binding activity assay results of selectedandrogen receptor modulator compounds of present invention and thestandard reference compounds on AR, as well as the cross-reactivity ofselected compounds on the PR, ER, MR and GR receptors, are shown inTables 1-2 below. Efficacy is reported as the percent maximal responseobserved for each compound relative to the reference agonist andantagonist compounds indicated above. Also reported in Tables 1-2 foreach compound is its antagonist potency or IC₅₀ (which is theconcentration (nM), required to reduce the maximal response by 50%), itsagonist potency or EC₅₀ (nM).

TABLE 1 Cotransfection and competitive binding data of selected androgenreceptor modulator compounds of present invention and the referenceagonist compound, dihydrotestosterone (DHT), and reference antagonistscompound, 2-hydroxyflutamide (Flut) and Casodex (Cas), on AR. AR AgonistAR Antagonist AR CV-1 Cells CV-1 Cells Binding Cmpd Efficacy PotencyEfficacy Potency K_(i) No. (%) (nM) (%) (nM) (nM) 204 34 2022 72 27 54218 78 2.0 na na 4.4 219 73 1.3 na na 50 220 68 1280 54 29 222 221 114 23 na na 147 222 81 2.2 na na 6.3 223 95 0.15 na na 1.0 224 108  41 nana 206 225 90 0.4 na na 0.9 227 na na 73 14 38 232 55 3.4 na na 7.6 23877 5.3 na na 17 239 83 2.0 na na 7.4 241 73 2.9 na na 30 242 66 2.8 nana 32 246 115  0.35 na na 7.1 254 78 0.90 na na 12 255 135  25 na na 67259 97 1.9 na na 6.3 262 58 5.9 na na 29 269 85 11 na na 14 272 na na 677.0 >1000 274 67 1.6 na na 1.4 280 78 2.2 na na 2.4 285 111  1.0 na na6.2 287 34 8.3 53 4.1 >1000 290 37 32 50 50 >1000 295 30 50 49 3.6 86297 43 22 43 3.2 58 307 na na 43 3.2 61 311 42 143 38 13 12 314 83 5.3na na 4.6 328 93 1.7 na na 48 330 81 3.9 na na 55 331 44 21 42 5.7 >1000332 121  14 na na 19 341 na na 85 15 277 347 na na 89 59 970 348 na na81 24 62 350 73 29 na na 165 351 79 23 na na 31 352 113  12 ma na 25 36536 55 43 14 124 366 na na 85 31 >1000 374 77 2.2 na na 6.2 377 89 0.45na na 1.4 381 72 1.8 na na 7.8 423 57 86 na na 22 426 93 45 na na 28 43296 8.0 na na 32 433 120  6.4 na na 1.5 444 83 73 na na 26 445 104  26 nana 5.8 449 83 16 na na 8.4 457 85 3.0 na na 3.2 474 73 0.60 na na 1.8490 113  12 na na 12 501 110  5.8 na na 16 513 na na 84 26 37 514 na na87 55 79 520 na na 76 58 36 523 29 1000 62 24 16 526 na na 89 43 161 52836 1300 59 26 nd 532 na na 85 73 159 535 na na 76 60 >1000 536 na na 7628 188 559 na na 92 122 118 571 na na 69 14 71 581 39 65 23 5000 24 582na na 92 26 43 602 na na 85 27 45 615 23 2800 82 48 56 616 na na 92 1715 630 30 221 67 13 109 632 na na 75 36 112 633 33 38 51 7.5 97 645/64648 848 68 4.1 36 647 42 233 64 31 81 655 na na 70 70 >1000 659 na na 7044 40 667 na na 89 27 7.4 675/676 na na 93 57 192 689 na na 89 40 132694 25 935 90 64 >1000 698 na na 84 17 32 721 na na 85 32 >1000 725 nana 87 79 >1000 737 na na 92 89 >1000 738 na na 91 27 >1000 741 na na 9227 322 753 na na 76 51 74 758 na na 94 87 3.6 762 na na 81 63 nd 764 nana 87 30 16 HO-Flut na na 83 25 34 Casodex na na 81 201 117 DHT 100  4.3na na 1.7 na = not active (i.e. efficacy of <20 and potency of >10,000);nd = not determined.

TABLE 2 Co-transfection and competitive binding data for selectiveprogesterone receptor modulator compounds of present invention and thereference agonist compound, progesterone (Prog), and referenceantagonists compound, RU486 on PR. PR Agonist PR Antagonist PR CV-1Cells CV-1 Cells Binding Cmpd Efficacy Potency Efficacy Potency K_(i)No. (%) (nM) (%) (nM) (nM) 242 na na 95 200 70 251 na na 91 747 930 473na na 55 880 508 631 na na 75 796 136 667 na na 89  70 144 671 na na 62200 >1000 689 105 2700 47  35  23 695 na na 90  20 203 697 na na 58316 >1000 725 na na 92 149 400 727 na na 90 108 161 731 na na 89  64 154735 na na 84 326 915 Prog 100 2.9 na na 3.5 ZK299 na na 95 2.2 18 na =not active (i.e. efficacy of <20 and potency of >10,000)

Pharmacological and Other Applications

As will be discernible to those skilled in the art, the androgen orprogesterone receptor modulator compounds of the present invention canbe readily utilized in pharmacological applications where AR or PRantagonist or agonist activity is desired, and where it is desired tominimize cross reactivities with other steroid receptor related IRs. Invivo applications of the invention include administration of thedisclosed compounds to mammalian subjects, and in particular to humans.

The following Example provides illustrative pharmaceutical compositionformulations:

EXAMPLE 468

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) COMPOUND 219 140 Starch, dried 100 Magnesiumstearate 10 Total 250 mg

The above ingredients are mixed and filled into hard gelatin capsules in250 mg quantities.

A tablet is prepared using the ingredients below:

Quantity (mg/capsule) COMPOUND 219 140 Cellulose, microcrystalline 200Silicon dioxide, fumed 10 Stearic acid 10 Total 350 mg

The components are blended and compressed to form tablets each weighing360 mg.

Tablets, each containing 60 mg of active ingredient, are made asfollows:

Quantity (mg/capsule) COMPOUND 219 60 Starch 45 Cellulose,microcrystalline 35 Polyvinylpyrrolidone (PVP) 4 (as 10% solution inwater) Sodium carboxymethyl starch (SCMS) 4.5 Magnesium stearate 0.5Talc 1.0 Total 150 mg

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution of PVP is mixed withthe resultant powders, which are then passed through a No. 14 mesh U.S.sieve. The granules so produced are dried at 50° C. and passed through aNo. 18 mesh U.S. sieve. The SCMS, magnesium stearate, and talc,previously passed through a No. 60 mesh U.S. sieve, and then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

Suppositories, each containing 225 mg of active ingredient, may be madeas follows:

COMPOUND 219   225 mg Saturated fatty acid glycerides 2,000 mg Total2,225 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of normal 2 g capacity and allowed to cool.

An intravenous formulation may be prepared as follows:

COMPOUND 219 100 mg Saturated fatty acid glycerides 1,000 mL Total 100mL

The compound is dissolved in the glycerol and then the solution isslowly diluted with isotonic saline. The solution of the aboveingredients is then administered intravenously at a rate of 1 mL perminute to a patient.

While description of the preferred embodiments and processing conditionshave been provided, the scope of the invention is not to be limitedthereto or thereby. Various modifications and alterations of the presentinvention will be apparent to those skilled in the art without departingfrom the scope and spirit of the present invention.

The invention is further described below in the form of non-limitingenumerated embodiments.

What is claimed is:
 1. A compound having the formula:

wherein: R¹ and R² are each independently selected from the group ofCOR³, CSR³, SO₂R³, NO, NR³R⁴, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,C₁-C₈ haloalkyl, C₂-C₈ haloalkenyl, C₂-C₈ haloalkynyl, C₁-C₈heteroalkyl, C₂-C₈ heteroalkenyl, C₂-C₈ heteroalkynyl, (CH₂)_(n)R^(3A),aryl, and heteroaryl, wherein the aryl, and heteroaryl are optionallysubstituted with F, Cl, Br, I, OH, OR³, NR³R⁴, CN, NO₂, SR³, SO₂R³,SO₂R³, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl; or R¹ and R²taken together form a three- to nine-membered alkyl, alkenyl,heteroalkyl, or heteroalkenyl nonaromatic ring, wherein the alkyl,alkenyl, heteroalkyl, or heteroalkenyl ring are optionally substitutedwith F, Cl, Br, I, OH, OR³, NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄heteroalkyl; R³ is selected from the group of C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₉ alkynyl, C₁-C₈ haloalkyl, and C₁-C₈ heteroalkyl; R^(3A)is aryl or heteroaryl, wherein the aryl and heteroaryl is optionallysubstituted with halogen, CN, NO₂, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄heteroalkyl; R⁴ is selected from the group of hydrogen, C₁-C₄ alkyl,C₁-C₄ haloalkyl and C₁-C₄ heteroalkyl; R⁵ is selected from the group ofhydrogen, F, Cl, Br, I, OR³, and C₁-C₄ alkyl; R⁶ is selected from thegroup of F, Cl, Br, I, CH₃, CF₃, CHF₂, CFH₂, CN, CF₂Cl, CF₂OR³, OR³,SR³, SO₂R³, SO₂R³, CO₂R³, NR³R⁴, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄ haloalkynyl, C₁-C₄heteroalkyl, C₂-C₄ heteroalkenyl, and C₂-C₄ heteroalkynyl; R⁷ isselected from the group of hydrogen, F, Cl, Br, I, CN, OH, OR³, C₁-C₈alkyl, C₁-C₈ haloalkyl, and C₁-C₈ heteroalkyl; R⁸ is hydrogen orhalogen; R⁹ is selected from the group of hydrogen, F, Br, Cl, I, OH,OR³, NR³R⁴, SR³, SO₂R³, SO₂R³, C₁-C₄ alkyl, C₁-C₄ haloalkyl and C₁-C₄heteroalkyl; R¹⁰ is selected from the group of:

R¹⁶ is selected from the group of hydrogen, C₁-C₈ alkyl, C₁-C₈haloalkyl, C₁-C₈ heteroalkyl, CH₂R^(3A), aryl, heteroaryl, COR¹⁷,CO₂R¹⁷, and CONR¹⁷R¹⁷; R¹⁷ is selected from the group of hydrogen, C₁-C₄alkyl, C₁-C₄ haloalkyl and C₁-C₄ heteroalkyl; R²⁴ is hydrogen, OH orOR³; R²⁵ and R³⁰ are each independently selected from the group ofhydrogen, F, Cl, Br, I, OH, OR³, NR³R⁴, SR³, SO₂R³, SO₂R³, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkynyl and C₂-C₆ alkenyl,wherein the alkyl, haloalkyl, and heteroalkyl are optionally substitutedwith F, Cl, Br, I, OR³, NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄heteroalkyl, aryl or heteroaryl, and wherein the aryl and heteroaryl areoptionally substituted with F, Cl, Br, I, CN, NO₂, OH, OCH₃, CF₃ orC₁-C₄ alkyl; or R²⁶ through R²⁹ are each independently selected from thegroup of hydrogen, F, Cl, Br, I, OH, OR³, NR³R⁴, SR³, SOR³, SO₂R³, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkynyl and C₂-C₆alkenyl; or any two of R²⁵ R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ taken togetherform a three to seven-membered alkyl or alkenyl or nonaromaticheteroalkyl ring; or any four of R²⁵, R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ takentogether form a fused aromatic ring; X is NR¹⁶; Y is selected from thegroup of O, S, NR³, NOR³ and CR³R⁴; Z is selected from the group of O,S, NR³, C═O, and CR²⁵R²⁶; or Z is two hydrogens; and n is 1, 2 or 3; andpharmaceutically acceptable salts thereof.
 2. A compound of claim 1,wherein: R³ is C₁-C₆ alkyl; R^(3A) is optionally substituted aryl orheteroaryl; R⁴ is hydrogen or C₁-C₄ alkyl; R⁵ is selected from the groupof hydrogen,halogen and optionally substituted C₁-C₆ alkyl; R⁷ ishydrogen or halogen; R⁸ is hydrogen; and R⁹ is hydrogen or halogen.
 3. Acompound of claim 2, wherein: R²⁵ and R³⁰ are each independentlyselected from the group of hydrogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ heteroalkyl, wherein the alkyl, haloalkyl, and heteroalkyl areoptionally substituted with F, Cl, OR³, NR³R⁴, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ heteroalkyl, aryl or heteroaryl, and wherein the aryland heteroaryl are optionally substituted with F, Cl, Br, I, CN, NO₂,OH, OCH₃, CF₃ or C₁-C₄ alkyl; R²⁶ through R²⁹ are each independentlyhydrogen, OH, C₁-C₆ alkyl or C₁-C₆ haloalkyl; and Y is selected from thegroup of O, S, and NOR³.
 4. A compound of claim 1, wherein: R¹ and R²are each independently selected from the group of COR³, CSR³, SO₂R³, NO,NR³R⁴, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ haloalkyl, C₂-C₈haloalkenyl, C₂-C₈ haloalkynyl, C₁-C₈ heteroalkyl, C₂-C₈ heteroalkenyl,C₂-C₈ heteroalkynyl, (CH₂)_(n)R^(3A), aryl, and heteroaryl, wherein thearyl, and heteroaryl are optionally substituted with F, Cl, Br, I, OR³,NR³R⁴, CN, NO₂, SR³, SOR³, SO₂R³, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄heteroalkyl ; R³ is C₁-C₆ alkyl; R^(3A) is optionally substituted arylor heteroaryl; R⁴ is hydrogen or C₁-C₆ alkyl; R⁵ is selected from thegroup of hydrogen, halogen and optionally substituted C₁-C₆ alkyl; R⁷ ishydrogen or halogen; R⁸ is hydrogen; R⁹ is hydrogen or halogen; R¹⁶ ishydrogen; R²⁵ and R³⁰ are each independently selected from the group ofhydrogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, whereinthe alkyl, haloalkyl, and heteroalkyl are optionally substituted with F,Cl, OR³, NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ heteroalkyl, aryl orheteroaryl, and wherein the aryl and heteroaryl are optionallysubstituted with F, Cl, Br, I, CN, NO₂, OH, OCH₃, CF₃ or C₁-C₄ alkyl;R²⁶ through R²⁹ are each independently hydrogen, OH, C₁-C₆ alkyl, orC₁-C₆ haloalkyl; and Y is selected from the group of O, S, and NOR³. 5.A compound of claim 1, wherein: R¹ and R² taken together form a three-to nine-membered alkyl, alkenyl, heteroalkyl, or heteroalkenylnonaromatic ring, wherein the alkyl, alkenyl, heteroalkyl, orheteroalkenyl ring are optionally substituted with F, Cl, Br, I, OR³,NR³R⁴, C₁-C₄ alkyl, C₁-C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl; R³ is C₁-C₆alkyl; R^(3A) is optionally substituted aryl or heteroaryl; R⁴ ishydrogen or C₁-C₆ alkyl; R⁵ is selected from the group of hydrogen,halogen and optionally substituted C₁-C₆ alkyl; R⁷ is hydrogen orhalogen; R⁸ is hydrogen; R⁹ is hydrogen or halogen; R¹⁶ is hydrogen; R²⁵and R³⁰ are each independently selected from the group of hydrogen, OH,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, wherein the alkyl,haloalkyl, and heteroalkyl are optionally substituted with F, Cl, OR³,NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ heteroalkyl aryl orheteroaryl, and wherein the aryl and heteroaryl are optionallysubstituted with F, Cl, Br, I, CN, NO₂, OH, OCH₃, CF₃ or C₁-C₄ alkyl;R²⁶ through R²⁹ are each independently hydrogen, halogen, OH,C₁-C₆alkyl, or C₁-C₆ haloalkyl; and Y is selected from the group of O,S, and NOR³.
 6. A compound of claim 1, wherein: R¹ and R² are eachindependently selected from the group of COR³, CSR³, SO₂R³, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₁-C₈ haloalkyl, C₂-C₈ haloalkenyl, C₁-C₈ heteroalkyl,C₂-C₈ heteroalkenyl, CH₂R^(3A), aryl and heteroaryl, wherein the aryl orheteroaryl are optionally substituted with F, Cl, Br, CN, NO₂, OR³,NR³R⁴, SR³, COMe, COCF₃, C₁-C₄ alkyl, or C₁-C₄ haloalkyl; or R³ is C₁-C₈alkyl, C₂-C₈ alkenyl, C₁-C₈ haloalkyl, and C₁-C₈ heteroalkyl; R^(3A) isheteroaryl or aryl, wherein the heteroaryl and aryl are optionallysubstituted with F, Cl, Br, CN, OMe, SMe, C₁-C₄ alkyl, or C₁-C₄haloalkyl; R⁴ is selected from the group of hydrogen, C₁-C₄ alkyl, C₂-C₄alkenyl, C₁-C₄ haloalkyl, and C₁-C₄ heteroalkyl; R⁵ is selected from thegroup of hydrogen, F, Cl, Br, OH, OMe, and C₁-C₄ alkyl; R⁶ is selectedfrom the group of F, Cl, Br, CH₃, CF₃, CHF₂, CFH₂, CN, CF₂Cl, CF₂OR³,OR³, SR³, NR³R⁴, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₂-C₄haloalkenyl, C₁-C₄ heteroalkyl, and C₂-C₄ heteroalkenyl; R⁷ is selectedfrom the group of hydrogen, F, Cl, Br, OR³, NR³R⁴, SR³, C₁-C₈ alkyl,C₁-C₈ haloalkyl, and C₁-C₈ heteroalkyl; R⁸ is hydrogen; R⁹ is selectedfrom the group of hydrogen, F, Br, Cl, OR³, NR³R⁴, SR³, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; R¹⁰ is selected from the group of:

R¹⁶ is selected from the group of hydrogen, C₁-C₈ alkyl, C₁-C₈haloalkyl, C₁-C₈ heteroalkyl, COR¹⁷, CO₂R¹⁷, and CONR¹⁷ R¹⁷; R¹⁷ isselected from the group of C₁-C₄ alkyl, C₁-C₄ haloalkyl and C₁-C₄heteroalkyl; R²⁴ is hydrogen, OH, or OR³; R²⁵ and R³⁰ are eachindependently selected from the group of hydrogen, OH, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, wherein the alkyl, haloalkyl, andheteroalkyl are optionally substituted with F, Cl, OR³, NR³R⁴, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ heteroalkyl, aryl or heteroaryl, andwherein the aryl and heteroaryl are optionally substituted with F, Cl,Br, I, CN, NO₂, OH, OCH₃, CF₃ or C₁-C₄ alkyl; R²⁶ through R²⁹ are eachindependently selected from the group of hydrogen, F, Cl, Br, OR³,NR³R⁴, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl and C₂-C₆alkenyl; any two of R²⁵, R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ taken together forma three to seven-membered alkyl or alkenyl or heteroalkyl-nonaromaticring; or any four of R²⁵, R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ taken together forma fused aromatic ring; X is NR¹⁶; is selected from the group of O, S,NR³, NOH, and NOR³; Z is selected from the group of O, S, NR³, andCR²⁵R²⁶, or Z is two hydrogens; and n is 1 or
 2. 7. A compound of claim1, wherein: R¹ and R² are each independently selected from the group ofCOR³, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ haloalkyl, C₂-C₈ haloalkenyl,C₁-C₈ heteroalkyl, CH₂R^(3A), aryl, and heteroaryl, wherein the aryl andheteroaryl are optionally substituted with F, Cl, Br, OH, OMe, SH, OMe,SMe, CN, NO₂, CF₃, Me, COMe, or COCF₃; or R³ is C₁-C₆ alkyl or C₁-C₆haloalkyl; R^(3A) is heteroaryl or aryl, wherein the heteroaryl and arylare optionally substituted with F, Cl, Br, CN, OMe, C₁-C₄ alkyl, orC₁-C₄ haloalkyl; R⁴ is hydrogen or C₁-C₄ alkyl; R⁵ is selected from thegroup of hydrogen, F, Cl, OMe, and C₁-C₄ alkyl; R⁶ is selected from thegroup of F, Cl, Br, C₁-C₄ alkyl, C₁-C₄ haloalkyl CF₃, CHF₂, CFH₂, CN,CF₂Cl, CF₂OMe, and OMe; R⁷ is selected from the group of hydrogen, F,Cl, Me, OMe, and CF₃; R⁸ is selected from the group of hydrogen, F, andCl; R⁹ is selected from the group of hydrogen, F, Cl, OH, Me, OMe, andCF₃; R¹⁰ is selected from the group of:

R¹⁶ is selected from the group of hydrogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, COR¹⁷, CO₂R¹⁷, and CONR¹⁷R¹⁷; R¹⁷ is selected from the groupof C₁-C₄ alkyl, C₁-C₄ halo alkyl and C₁-C₄ heteroalkyl; R²⁴ is hydrogenor OH; R²⁵ and R³⁰ are each independently selected from the group ofhydrogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, whereinthe alkyl, haloalkyl, and heteroalkyl are optionally substituted with F,Cl, OR³, NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ heteroalkyl, aryl orheteroaryl, and wherein the aryl and heteroaryl are optionallysubstituted with F, Cl, Br, I, CN, NO₂, OH, OCH₃, CF₃ or C₁-C₄ alkyl;R²⁶ through R²⁹ are each independently selected from the group ofhydrogen, F, Cl, OH, OMe, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆heteroalkyl; or any two of R²⁵ R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ taken togetherform a four to six-membered alkyl or alkenyl nonaromatic ring; or anyfour of R²⁵ R²⁶, R²⁷, R²⁸, R²⁹ and R³⁰ taken together form a fusedaromatic ring; X is NR¹⁶; Y is selected from the group of O, S, andNOR³; Z is O or CR²⁵R²⁶; or Z is two hydrogens; and n is 1 or
 2. 8. Acompound of claim 1, wherein: R¹ and R² are each independently selectedfrom the group of C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ haloalkyl, C₁-C₈heteroalkyl, and CH₂R^(3A); or R³ is C₁-C₆ alkyl, or C₁-C₆ haloalkyl;R^(3A) is heteroaryl or aryl, wherein the heteroaryl and aryl areoptionally substituted with F, Cl, Br, CN, CF₃, OMe, or C₁-C₄ alkyl; R⁴is hydrogen; R⁵ is selected from the group of hydrogen, F, Cl, OMe, andMe; R⁶ is selected from the group of F, Cl, C₁-C₄ alkyl, CF₃, CHF₂,CFH₂, CF₂Cl, CF₂OMe, and OMe; R⁷ is selected from the group of hydrogen,F, Cl, Me, OMe; R⁸ is hydrogen; R⁹ is selected from the group ofhydrogen, F, Cl, Me, OMe, CF₃; R¹⁰ is selected from the group of:

R²⁴ is hydrogen or OH; R²⁵ and R³⁰ are each independently selected fromthe group of hydrogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆heteroalkyl, wherein the alkyl, haloalkyl, and heteroalkyl areoptionally substituted with F, Cl, OR³, NR³R⁴, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ heteroalkyl, aryl or heteroaryl, and wherein the aryland heteroaryl are optionally substituted with F, Cl, Br, I, CN, NO₂,OH, OCH₃, CF₃ or C₁-C₄ alkyl; R²⁶ through R²⁹ are each independentlyselected from the group of hydrogen, F, Cl, OH, OMe, C₁-C₄ alkyl, andC₁-C₄ haloalkyl; X is NH; Y is O or S; Z is CR²⁵R²⁶; and n is 1 or
 2. 9.A compound of claim 1, wherein R¹⁰ is represented by the formula:

wherein: R²⁵ and R³⁰ are each independently selected from the group ofhydrogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, whereinthe alkyl, haloalkyl, and heteroalkyl are optionally substituted with F,Cl, OR³, NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ heteroalkyl, aryl orheteroaryl, and wherein the aryl and heteroaryl are optionallysubstituted with F, Cl, Br, I, CN, NO₂, OH, OCH₃, CF₃ or C₁-C₄ alkyl;R²⁶ and R²⁹ are each independently selected from the group of hydrogen,F, Cl, Br, I, OH, OR³, NR³R⁴, SR³, SOR³, SO₂R³, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ heteroalkyl, C₂-C₆ alkynyl and C₂-C₆ alkenyl; R³ isselected from the group of hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₁-C₈ haloalkyl, and C₁-C₈ heteroalkyl; R⁴ is selected from thegroup of hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ heteroalkyl;and n is 1,2, or
 3. 10. A compound of claim 1, wherein R¹⁰ isrepresented by the formula:

wherein: R²⁵, R³⁰ are each independently selected from the group ofhydrogen, F, Cl, Br, I, OR³, NR³R⁴, SR³, SOR³, SO₂R³, COR³, CO₂R³, C₁-C₆alkyl, C₁-C₆ haloalkyl C₁-C₆ heteroalkyl, C₂-C₆ alkynyl and C₂-C₆alkenyl, wherein the alkyl, haloalkyl, and heteroalkyl are optionallysubstituted with aryl or heteroaryl, and wherein the aryl and heteroarylare optionally substituted with F, Cl, Br, I, CN, NO₂, OH, OCH₃, CF₃ orC₁-C₆ alkyl; R³ is selected from the group of hydrogen, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ haloalkyl, and C₁-C₈, heteroalkyl;and R⁴ is selected from the group of hydrogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, and C₁-C₄ heteroalkyl; n is 1, 2, or
 3. 11. A compound ofclaim 1, wherein R¹⁰ is represented by the formula:

wherein: R³⁰ is hydrogen, C₁-C₄ alkyl or C₁-C₄ haloalkyl; R^(A) isselected from the group of hydrogen, OR^(C), O₂CR^(C), (CH₂)_(n)OR^(C),NHR^(C), NHCOR^(C), F, Cl, Br, I, CN, SCN, and SCH₃; R^(B) is selectedfrom the group of hydrogen, F, Cl, Br, I, CHF₂, CF₃, C₁-C₆ alkyl, aryl,and heteroaryl, wherein the alkyl, aryl and heteroaryl are optionallysubstituted with F, Cl, Br, I, CN, NO₂, OH, OCH₃, CF₃, or C₁-C₄ alkyl;R^(C) is selected from the group of hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₁-C₈ haloalkyl, C₁-C₈ heteroalkyl, and(CH₂)_(n)R^(D); R^(D) is aryl or heteroaryl, optionally substituted withF, Cl, Br, I, CN, NO₂, OH, OCH₃, CF₃, or C₁-C₆ alkyl; and n is 1, 2, or3.
 12. A compound according to claim 1, wherein the compound is anandrogen receptor modulator.
 13. A compound according to claim 12,wherein the compound is an androgen receptor antagonist.
 14. A compoundaccording to claim 12, wherein the compound is an androgen receptoragonist.
 15. A compound according to claim 12, wherein the compound isan androgen receptor partial agonist.
 16. A compound according to claim1, wherein the compound is a progesterone receptor modulator.
 17. Acompound according to claim 16, wherein the compound is a progesteronereceptor antagonist.
 18. A compound according to claim 16, wherein thecompound is a progesterone receptor agonist.
 19. A compound according toclaim 16, wherein the compound is a progesterone receptor partialagonist.
 20. A compound according to claim 1, wherein the compound isselected from the group of:6-Dimethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 217);6-Diethylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 218);6-Dipropylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 219);6-Dibutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 220);6-Diisobutylamino-4-trifluoromethyl-2(1H)-quinolinone (Compound 221);6-(bis-Cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 222);6-(bis-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1)-quinolinone(Compound 223);6-(bis-2,2,3,3,3-Pentafluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 224);6-(bis-2-Chloro-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 225);6-(bis-2-Bromoethyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound226);6-(bis-N-2,2,2-Trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 228);6-(N-2,2,2-Chlorodifluoroethyl-N-2,2,2-Trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 229);6-(bis-N-2,2-Difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 230);6-(N-2,2-Dichloroethyl-N-2,2,2-trichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 231);6-(bis-N-2,2-Dichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 232);6-(N-2,2-Dichloroethyl-N-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 233);6-(N-2,2-Dichloroethyl-N-2,2,2-chlorodifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 234);6-(N-Isopropyl-N-methyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 235);6-(N-Methyl-N-cyclopentyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 236);6-(N-Methyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 237);6-(N-Ethyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound238); 6-(N-Ethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 239);6-(N-Ethyl-N-1-methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 240);6-(N-Ethyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 241);6-(N-Ethyl-N-2,2-dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 242);6-(N-Ethyl-N-cyclopentyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 243);6-(N-Ethyl-N-1-acetylethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 244);(±)-6-(N-Ethyl-N-1-methyl-2-hydroxypropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 245);6-(N-Ethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 246);6-(N-Ethyl-N-3-furylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 247);(±)-6-(N-Ethyl-N-2,2-dimethoxyisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 248);6-(N-Isopropyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 249);6-(N-2-Hydroxyethyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 250);(±)-6-(N-Propyl-N-1-methylbutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 251);(±)-6-(N-Propyl-N-1,2-dimethylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 252);6-(N-Propyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 253);6-(N-Propyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 254);(±)-6-(N-Propyl-N-1-methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 255);6-(N-2-Hydroxyethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 256);6-(N-Isopropyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 257);6-(N-Methyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 258);6-(N-2,2,2-trifluoroethyl-N-isobutyl)amino-4-triflouromethyl-2(1H)-quinolinone(Compound 259);6-(N-2,2,2-trifluoroethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 260);6-(N-2,2,2-Trifluoroethyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 261);(±)-6-(N-2,2,2-Trifluoroethyl-N-1-methylpropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 262);(±)-6-(N-2,2,2-Trfluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 263);(+)-6-(N-2,2,2-Trifluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 264);(−)-6-(N-2,2,2-Trifluoroethyl-N-2-chloroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 265);6-(N-2,2,2-Trifluoroethyl-N-3-furfuryl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 266);6-(N-2,2,2-Trifluoroethyl-N-3-thiophenemethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 267);6-(N-2,2,2-Trifluoroethyl-N-3,3-dimethylbutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 268);6-(N-2,2,2-Trifluoroethyl-N-2-thiophenemethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 269);6-(N-2,2,2-Tifluoroethyl-N-2-furfuryl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 270);6-(N-Butyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 271);6-(bis-N,N-Benzyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound272);6-(N-2,2,2-Trifluoroethyl-N-cyclobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 273);6-(N-2,2,2-Trifluoroethyl-N-2,2-dichloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 274);6-(N-2,2,2-Trifluoroethyl-N-2-chloroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 275);6-(N-Benzyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 276);6-(N-4-Fluorobenzyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 277);6-(N-Propyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 278);6-(N-2,2,3,3,3-Pentafluoropropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 279); 6-Diallylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 280);6-(N-Isobutyl-N-allyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 281);6-(N-Isopropyl-N-allyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 282);6-(N-Allyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 283);6-(N-Allyl-N-cyclopropylmethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 285);6-(N-Allyl-N-2,2,2-trifluoroacetyl)amino-4-trifluoromethyl-2(1)-quinolinone(Compound 286);6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroacetyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 287);6-(N-Allyl-N-propyl)amino-4-trifluoromethyl-2(1H)-quinolinone (Compound288);(±)-6-(N-2-Hydroxyisopropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 289);(±)-6-(N-Isobutyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 290);6-(N-2,2-Difluoroethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 291);6-(N-2,2-Dimethylpropyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 292);6-(N-2,2-Difluoro-2-chloroethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 293);6-(N-2,2-Difluoro-2-chloroethyl-N-2,2-difluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 294);6-(N-2,2,2-Trifluoroethyl-N-methylsufonyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 295);1-Methyl-6-(N-propyl-N-isobutyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 296);1-Methyl-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 297);1-Ethyl-6-(bis-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 298);6-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-trifluoromethyl-2(1H)-thioquinolinone(Compound 300);(±)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 301);(+)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 302);(−)-6-(N-2,2,2-Trifluoroethyl-N-2,2,2-trifluoroisopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 303); 6-(1-Piperdinyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 311); 6-(1-Pyrrolidinyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 312); 6-(1-Morpholino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 313);(±)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 314);(+)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 315);(−)-6-(2-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 316);6-(N-phenyl-N-ethylamino)-4-trifluoromethyl-2(1H)-quinolinone (Compound319);6-(N-phenyl-N-ethylamino)-4-trifluoromethyl-2-isopropyloxyquinoline(Compound 320);6-(N-phenyl-N-2,2,2-trifluoroethylamino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 321);(±)-6-(3-Methyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 322);6-(4-Methyl-1-piperidino)-4-triflouromethyl-2(1H)-quinolinone (Compound323);6-(cis-3,5-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 324);6-(2,6-cis-Dimethyl-1-piperidino)-4-triflouromethyl-2(1H)-quinolinone(Compound 325);6-(2,6-trans-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 326);(±)-6-(2-Methyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 327);6-(2,5-cis-Dimethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 328);(±)-6-(2,5-trans-Dimethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 329); 6-(1-Azepano)-4-trifluoromethyl-2(1H)-quinolinone(Compound 330);(±)-6-(2-Hydroxymethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 331);6-(2,5-cis-Dimethyl-1-pyrrolino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 332);(±)-6-(2-Propyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 333);(±)-6-(2-Methoxymethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 334);(±)-6-(2-Ethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 335);6-(1-Heptamethyleneimino)-4-trifluoromethyl-2(1H)-quinolinone (Compound336);(±)-6-(2-Ethoxycarbonyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 337);(±)-6-(2-Isopropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 338);(±)-6-(2-Hydroxycarbonyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 339);6-(3,5-cis-Dimethyl-1-piperazino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 340);(±)-6-(2-Benzyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 341);(±)-6-(5-Methyl-2-oxo-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 342);(±)-6-(2-(2-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 343);(±)-6-(3-Hydroxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 344);(±)-6-(3-Acetyloxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 345);(±)-6-(3-Hydroxy-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 346); 6-(1-Indolino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 347);6-(1-Tetrahydroquinolino)-4-trifluoromethyl-2(1H)-quinolinone (Compound348); 6-(2-Tetrahydroisoquinolino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 349);(±)-6-(1,3,3-Trimethyl-6-azabicyclo[3,2,1]octanyl-6-)-4-trifluoromethyl-2(1H)-quinolinone(Compound 350);(±)-6-(2-Trifluoromethyl-5-cis-methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 351);(±)-6-(2-Trifluoromethyl-5-trans-methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 352);(±)-6-(2-Trifluoromethyl-5-cis-ethyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 354);(±)-6-(2-Trifluoromethyl-5-trans-ethyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 355);(±)-6-(5-Methyl-1-oxazolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 356);6-(N-2,2,2-Trifluoroethyl-N-3,3,3-trifluoropropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 358);6-bis-N,N-Thiomethoxymethylamino-4-trifluoromethyl-2(1H)-quinolinone(Compound 361);(±)-6-(2,5-trans-Diethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 363);6-(2,5-cis-Diethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 364);(±)-6-(2,5-trans-Dipropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 365);6-(2,5-cis-Dipropyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 366);6-(2,5-cis-Dibutyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 368);(±)-6-(2,5-trans-Dibutyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 369); 6-(2,6-cis-Diethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound370);(±)-6-(2,6-trans-Diethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 371); 6-(2,6-cis-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone (Compound372);(±)-6-(2,6-trans-Dimethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 373);6-(N-Propyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 374);6-(bis-2,2,2-Trifluoroethyl)amino-4-methyl-2(1H)-quinolinone (Compound377);(±)-6-(2,5-trans-dimethyl-1-pyrrolidino)-4-methyl-2(1H)-quinolinone(Compound 379);6-(2,5-cis-dimethyl-1-pyrrolidino)-4-methyl-2(1H)-quinolinone (Compound380);6-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 381);6-(bis-N,N-2,2,2-Chlorodifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 383);6-(N-2,2,2-Chlorodifluoroethyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 384);6-(N-Ethyl-N-2,2,2-trifluoroethyl)amino-4-methyl-2(1H)-quinolinone(Compound 386); 6-N,N-Diethylamino-4-methyl-2(1H)-quinolinone (Compound387); 6-(bis-2,2,2-trifluoroethyl)amino-4-ethyl-2(1H)-quinolinone(Compound 388);6-(bis-2,2,2-trifluoroethyl)amino-4-isopropyl-2(1H)-quinolinone(Compound 391);7-Fluoro-6-(bis-trifluoroethyl)amino-4-trifluoro(methyl-2(1H)-quinolinone(Compound 393);8-Fluoro-6-(N-2,2,2-trifluoroethyl-N-isopropyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 401);3-Fluoro-6-(bis-2,2,2-trifluorofluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 404); 6-(bis-Isobutylamino)-4-methyl-2(1H)-quinolinone(Compound 405);3-Fluoro-6-(N-methyl-N-2,2,2-trifluorofluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 406);6-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-methoxy-2(1H)-quinolinone(Compound 411);6-(bis-N,N-2,2,2-Trifluoroethyl)amino-4-difluoromethyl-2(1H)-quinolinone(Compound 413);4-Chloro-6-(bis-N,N-2,2,2-trifluoroethyl)amino-2(1H)-quinolinone(Compound 417);(R)-6-(2-Hydroxymethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 421);(R)-6-(2-Methoxymethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 423);(±)-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 424);(±)-6-(2-Cyanothiomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 425);(±)-6-(2-Thiomethoxymethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 426);(±)-6-(2-Cyanomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 427);(±)-6-(2-Bromomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 428);(±)-6-(2-Iodomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 429);(+)R-6-(2-Iodomethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 430);(±)-6-(2-Fluoromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 431);(+)S-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 432);(−)R-6-(2-Chloromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 433);(+)R-6-(2-Chloromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 434);(−)S-6-(2-Chloromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 435);R-6-(2-Difluoromethyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 436);(±)-6-(2-(1l-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 437);(±)-6-(2l-(1u-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-triflouromethyl-2(1H)-quinolinone(Compound 438);(±)-6-(2-Formyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 439);(±)-6-(2-Difluoromethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 440);(±)-6-(2-Aminomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 441);(R)-6-(2-Vinyl-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 442);(R)-6-(2-Formyl-1-pyrrolidino)-4-triflouromethyl-2(1H)-quinolinone(Compound 443);(±)-6-(2-Vinyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 444);(±)-6-(2-Benzyloxyethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 445);(±)-6-(2-(2,2-Difluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 446);(±)-6-(2-Trifluoroacetamidomethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 447);(±)-6-(2-(2-Ethoxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 448);(±)-6-(2-(4-Trifluoromethyl)benzyloxyethyl-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 449);(+)-6-(2R-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 450);(−)6-(2R-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 451);6-(2S-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 452);6-(2S-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-pyrrolidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 453);(±)-6-(2l-(1-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 454);(±)-6-(2l-(1u-Hydroxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 455);(−)-6-(2S-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 456);(+)-6-(2R-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 457);(+)-6-(2R-(1S-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 458);(−)-6-(2S-(1R-Hydroxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 459);(±)-6-(2l-(1-Acetyloxyethyl)-1-piperidino)-4-triflouromethyl-2(1H)-quinolinone(Compound 460);(±)-6-(2l-(1u-Acetyloxyethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 461);(±)-6-(2l-(1u-Methoxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 462);(±)-6-(2l-(1l-Methoxy-2,2,2-trifluoroethyl)-1-piperidino)-4-trifluoromethyl-2(1H)-quinolinone(Compound 463);7-Methoxy-6-(N-methyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 464);7-Methoxy-6-(N-ethyl-N-2,2,2-trifluoroethyl)amino-4-trifluoromethyl-2(1H)-quinolinone(Compound 468);6-(N-Cyclopropylmethyl-N-2,2,2-trifluoroethyl)amino-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 470);6-(N-Cyclopropylmethyl-N-2,2,2-trifluoroethyl)amino-7-hydroxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 471);6-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-7-methoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 472);6-(N-Isobutyl-N-2,2,2-trifluoroethyl)amino-7-hydroxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 473);6-(bis-N,N-2,2,2-trifluoroethyl)amino-5-methoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 600);6-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-propyloxy-4-trifluoromethyl-2(1H)-quinolinone:(Compound 604);6-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-ethoxy-4-trifluoromethyl-2(1H)-quinolinone(Compound 607);6-(bis-N,N-2,2,2-Trifluoroethyl)amino-5-chloro-4-trifluoromethyl-2(1H)-quinolinone(Compound 612); 6-Cyclohexyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 616);6-Cyclohexyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound618);6-(1-Hydroxy-3,3,5,5-tetramethyl)cyclohexyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 625);6-(3,3,5,5-Tetramethyl)cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 626);6-(5,5-Dimethycyclopentenyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 627);6-(2,2-Dimethycyclopentyl)-4-trifluoromethyl-2(1H)-quinolinone (Compound628); 6-(1-Hydroxycyclohexyl)-4-trifluoromethyl-2(1H)-quinolinone(Compound 629); 6-Cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 630); 6-Cyclohexyl-4-triflouromethyl-2(1H)-thioquinolinone(Compound 631); 6-Cyclopentenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 632); 6-Cycloheptenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 633);6-Cyclohexenyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound635); 6-Cyclohexyl-7-methoxy-4-trifluoromethyl-2(1H)quinolinone(Compound 636);6-Cyclopentyl-3-fluoro-4-trifluoromethyl-2(1H)-quinolinone (Compound638); (Z)-6-(1-Propyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 639);(E)-6-(1-Propyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound640); 6-(1-Propyl)butyl-4-trifluoromethyl-2(1H)-quinolinone (Compound641); (E)-6-(1-Methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 642);(Z)-6-(1-Methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound643); (±)-6-(1-Methyl)butyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 644);(E)-6-(1-Ethyl-1-)propenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound645); (Z)-6-(1-Ethyl-1-)propenyl-4-trifluoroethyl-2(1H)-quinolinone(Compound 646); 6-(1-Ethyl)propyl-4-triflouromethyl-2(1H)-quinolinone(Compound 647);6-(1-Isopropyl-2-methyl-1-)propenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 648);6-(1-Isopropyl-2-methyl)propyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 649);(Z)-6-(1-Isobutyl-3-methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 650);(E)-6-(1-Isobutyl-3-methyl-1-)butenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 651);6-(1-Isobutyl-3-methyl)butyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 652);6-(1-Propyl)butyl-4-trifluoromethyl-2(1H)-thioquinolinone (Compound653); 6-(3-Oxo-1-)cyclopentenyl-4-trifluoromethyl-2(1H)-quinolinone(Compound 654);6-(3-Oxo-1-)cyclohexenyl-4-trifluoromethyl-2(1H)-quinolinone (Compound655);6-(3-Oxo-1-)cyclopentenyl-3-methyl-4-difluoromethyl-2(1H)-quinolinone(Compound 656);6-(3-Oxo-1-)cyclohexenyl-3-methyl-4-difluoromethyl-2(1H)-quinolinone(Compound 657);4-Trifluoromethyl-6-(1-(3,3,3-trifluoropropyl)-1(E)-propenyl)-2(1H)-quinolinone(Compound 774);4-Trifluoromethyl-6-(1-ethyl-4,4,4-trifluoro-1(E)-butenyl)-2(1H)-quinolinone(Compound 776);4-Trifluoromethyl-6-(1-ethyl-4,4,4-trifluoro-1(Z)-butenyl)-2(1H)-quinolinone(Compound 777);.
 21. A method for affecting androgen receptor activityin a mammal, comprising administering to said mammal a compoundaccording to claim
 1. 22. A method for affecting progesterone receptoractivity in a mammal, comprising administering to said mammal a compoundaccording to claim
 1. 23. A method for modulating a process in a mammalmediated by androgen receptors, comprising administering to a mammal apharmaceutically effective amount of a compound according to claim 1.24. A method for modulating a process in a mammal mediated byprogesterone receptors, comprising administering to a mammal apharmaceutically effective amount of a compound according to claim 1.